Homocysteine: Diagnostic Significance and Clinical Insights

Authors: Dr. Payal Bhandari, M.D., Hailey Chin

Contributors: Vivi Chador, Amer Džanković, Nigella Umali Ruguian

Homocysteine 

Homocysteine is a type of amino acid used to make proteins. Normally, vitamin B12, vitamin B6, and folic acid (vitamin B9) break down homocysteine, transforming the majority of it into other substances the body needs. If functioning optimally, very little homocysteine is found in the blood. Abnormally high homocysteine levels can indicate a B vitamin deficiency linked to malnutrition or gut malabsorption, and is associated with an increased risk for cardiovascular disease, thyroid dysfunction, and other disorders.

Typical Adult Range

Ranges and thresholds can vary due to: 

(1) Lab-specific equipment, techniques, and chemicals, and 

(2) Patient demographics, including age, sex, and ethnicity.

Key Insights

Homocysteine (Hcy) is an amino acid made when the body breaks down methionine, found in protein-rich foods. Hcy helps recycle molecules and build proteins. Methionine is converted to S-adenosyl-L-methionine (SAMe), which helps make hormones and other chemicals. SAMe turns into -Adenosyl-L-Homocysteine (SAH), which becomes Hcy. With enough B vitamins (B6, B9, B12), Hcy either turns back into methionine or becomes cysteine. High Hcy levels can signal problems with protein breakdown or B vitamin deficiencies. Low Hcy might mean too many B vitamins or fast conversion to cysteine, lowering glutathione (GSH), an important antioxidant. Measuring Hcy and B vitamin levels can help identify health issues, guide diet and supplements, and improve treatment for chronic conditions.

 What is Homocysteine?

Definition of Homocysteine

Homocysteine (Hcy) is made when the body breaks down dietary protein. It helps recycle molecules, build new proteins, and support metabolism. Vitamins B6, B9, and B12 help keep Hcy levels low in the blood.

Physiology of Homocysteine1

Homocysteine (Hcy) is made when the body breaks down methionine, an amino acid in protein-rich foods. Methionine contains sulfur and helps create other essential amino acids.

Amino Acids are the Building Blocks of Protein

Proteins are made of amino acids, the building blocks of life. Each amino acid has an amino group (-NH2), carboxyl group (-COOH), and unique side chain (R). Of the 20 amino acids essential for protein synthesis, some must be obtained from food. Amino acids link via peptide bonds into chains, with their sequence determining protein shape and function. Even minor changes can impact function, causing diseases or enhancing activity. 

Figures 1: Essential and Non-Essential Amino Acids

Protein Metabolism and Synthesis in the Body

Figure 2: Protein cannot be stored and is broken into amino acids for new proteins, nonessential amino acids, and nitrogen compounds. Excess protein converts to glycogen or fat for energy or metabolic pathways.

 

Formation of Homocysteine

Homocysteine (Hcy) forms in the body after eating foods high in methionine, like meat, nuts, and oils. Here’s the process:

  • Methionine Activation: Methionine gets an energy group from ATP.

  • Methyl Group Transfer: Enzymes add a methyl group to methionine, forming SAMe, which donates the group to DNA, RNA, and proteins, turning into SAH.

  • SAH Breakdown: An enzyme splits SAH into adenosine and Hcy.

  • Hcy Circulation: Most Hcy binds to albumin in the blood, with 99% reabsorbed by the kidneys and 1% excreted in urine.

  • Remethylation: Hcy turns back into methionine with folate, MTHFR, and vitamin B12.

  • Transsulfuration: Hcy combines with serine to form cystathionine, helped by vitamin B6, which breaks down into cysteine for making antioxidants like glutathione.

 

Figure 3: Homocysteine (Hcy) follows two pathways in cells: one turns it into methionine, and the other into cystathionine. These processes are controlled by SAM and SAH, which depend on vitamins B6, B9, and B12. SAM and SAH help make important molecules like creatine, detoxify the body, produce energy (ATP), and support neurotransmitters.

 (DHFR = dihydrofolate reductase; THF = tetrahydrofolate; SHMT = serine hydroxymethyltransferase; MTHF = methylenetetrahydrofolate; MTHFR = 5,10-methylene-THF reductase; ATP = adenosine triphosphate; MAT = methionine adenosyltransferase; ADP = adenosine diphosphate; SAM = S-adenosylmethionine; SAH = S-adenosylHcy; BHMT = betaine-Hcy S-methyltransferase; CBS = cystathionine β-synthase; CSE = cystathionase; GSH = glutathione; H2S = hydrogen sulfide).

 

Role of Homocysteine in the Body

Homocysteine stores cysteine, which is used to produce glutathione (GSH), a powerful antioxidant. GSH has key roles in the body:

  • Protects cells, especially mitochondria, from damage by harmful molecules like ROS and inflammation.

  • Supports liver detox by helping remove harmful substances.

  • Eliminates toxins, including ROS and peroxides.

  • Aids in immune responses and controls inflammation.

  • Keeps vitamins C and E active as antioxidants.

  • Helps repair DNA, proteins, and other cell parts.

  • Supports brain function and mood regulation.

  • Boosts immune and nerve cell health.

  • Transports amino acids for cell health and longevity.

  • Low levels of GSH are linked to aging and conditions like cancer, heart disease, and neurodegenerative disorders.

Regulation of Homocysteine

Homocysteine (Hcy) levels are influenced by hormones, diet, and medications. Vitamins B6, B9, and B12, found in dark green veggies, legumes, and whole grains like quinoa, wheat, oats, and brown rice, help control Hcy levels and reduce the risk of tissue damage from high Hcy and oxidative stress.

 

Hormonal Regulation

Insulin helps lower homocysteine (Hcy) by turning it into methionine, which reduces cysteine and glutathione (GSH) production. It also supports fat metabolism and energy (ATP), which are important for DNA, RNA, and cell repair while keeping harmful ROS low. When insulin is low, blood sugar rises, Hcy levels increase, cysteine drops, and ATP production slows, causing more ROS and cell damage.

 

Cortisol, a stress hormone, raises Hcy by breaking down proteins or turning food into glucose. This releases Hcy-building blocks. High cortisol from stress also increases ROS, which damages cells. Vitamin C can lower both Hcy and cortisol levels, reducing stress on the adrenal glands.

 

Diet

Your diet affects the levels of proteins and amino acids in your blood, which impacts your health. For example, methionine (Met), found in meat, nuts, and legumes, can raise homocysteine (Hcy) levels if eaten in excess. High Hcy is linked to health problems. Eating foods rich in B6 and B9 (like dark green vegetables) helps lower Hcy by supporting key body processes. Polyphenols in foods like tea, coffee, berries, and fermented items can reduce nutrient absorption (e.g., iron and zinc). While polyphenols protect cells and support gut health, too many can interfere with nutrient processing. Eating too much methionine or polyphenol-rich foods can raise Hcy levels, lower antioxidants like glutathione, and harm blood health over time.

Figure 4: Eating too much protein from animal products and nuts can stop the body from properly recycling homocysteine (Hcy), raising Hcy levels. A lack of B vitamins, found in green vegetables and a healthy gut, can change the MTHFR enzyme gene, disrupting important body processes. This leads to a faster breakdown of glutathione (GSH), a key antioxidant. The enzyme GGT and hydrogen sulfide (H2S) speed up cell damage, harming organs and tissues.

Drugs

Smoking reduces blood flow, increases cortisol, and raises blood sugar, which creates harmful proteins like TNF-alpha, interleukins, and reactive oxygen species (ROS). The cadmium in nicotine lowers the effectiveness of antioxidants like vitamins C and E, and glutathione, and reduces hormone production, including serotonin and melatonin.

 

Alcohol and its breakdown products affect liver genes and DNA. Acetaldehyde, a byproduct of alcohol, disrupts the conversion of homocysteine to methionine, lowering cysteine and glutathione production and increasing homocysteine levels. Long-term alcohol use can damage the liver, cause inflammation and scarring, and lead to liver failure. Studies show that limiting alcohol intake helps maintain stable homocysteine levels and supports glutathione production.

Figure 5: Acetaldehyde, a byproduct of alcohol, disrupts the balance between SAM and SAH. This causes more homocysteine (Hcy) to turn into methionine, reducing cysteine and glutathione (GSH) production. Lower GSH levels increase the risk of tissue damage from oxidative stress and affect functions like making molecules and neurotransmitters, detoxifying and balancing hormones, and producing energy.

 

Pharmaceutical Medications

Long-term use of certain drugs can affect the body’s ability to absorb B vitamins and interfere with liver processes. Some drugs also use a lot of heme iron, which reduces iron and oxygen for other organs, possibly causing tissue damage and increasing harmful molecules. 

Drug-induced liver injury (DILI) is a leading cause of acute liver failure and can be life-threatening. It is also a common reason for drugs to be withdrawn from the market. There are two types of DILI: intrinsic and idiosyncratic.

  • Intrinsic DILI happens in predictable patterns, such as taking over 7.5g of acetaminophen (APAP) in one dose, which can cause liver damage. Even the approved 4g/day dose for two weeks can raise liver enzyme levels in about a third of patients.

  • Idiosyncratic DILI (IDILI) is harder to predict and doesn’t depend on the dose. It can take weeks or months to develop and causes 10-15% of acute liver failure in the U.S. Factors like an unhealthy gut microbiome and blood vessel inflammation can increase the risk of drug reactions. Repeated drug use worsens liver damage, affecting protein and fat processing.

DILI can resemble a viral liver infection, but diagnosing it is difficult. Liver biopsies often don’t help, as symptoms are similar to other liver conditions. A higher number of eosinophils (white blood cells) is rare in DILI cases.

Figure 6: Drug-Induced Liver Injury. The accumulation and metabolism of drugs in the liver can cause a variety of pathophysiologic complications.  

 

Clinical Significance of High Homocysteine Levels

                      

Figure 7: Decoding Homocysteine’s Role in Health

 

Homocysteine (Hcy) is a useful marker for detecting health issues. High Hcy levels are linked to shorter lifespans. Deficiencies in vitamins B6, B9 (folate), or B12 lower antioxidant activity and increase harmful molecules like reactive oxygen species (ROS) and proinflammatory proteins. ROS can damage genes that produce blood cells, platelets, and metabolic proteins. For example, ROS can mutate the MTHFR gene, reducing Hcy conversion to methionine and raising Hcy levels. Mutations in the CBS gene also increase Hcy levels by affecting cystathionine conversion. Reduced cysteine storage raises gamma-glutamyl transferase (GGT) in the liver and kidneys, breaking down glutathione (GSH), an antioxidant. Lower GSH leads to faster tissue damage.

 

Atherosclerosis-Induced Vascular Inflammation

High homocysteine (Hcy) levels can lead to a number of health problems. In the bloodstream, low antioxidant levels make cholesterol more likely to oxidize, triggering a process called atherosclerosis. This narrows arteries, raises blood pressure, and causes damage to organs like the liver, heart, and pancreas.

Figure 8: Atherosclerosis causes artery thickening (tunica intima hyperplasia) and clot formation by platelets. Macrophages ingest oxidized LDL cholesterol, becoming foam cells that release inflammatory proteins and ROS. Chronic inflammation increases white blood cells and platelets, damaging cells and microbiota, reducing organ function, and raising the risk of health issues.

Liver Dysfunction and Damage

The liver’s role in processing fats, proteins, and balancing energy is disrupted by high Hcy, leading to fat buildup and inflammation. This can activate white blood cells (WBCs), causing more damage and reducing the body’s ability to fight off disease.

Figure 9:  Chronic liver disease (steatosis, steatohepatitis, and cirrhosis, respectively, based on severity of progression) is associated with decreased harvesting of energy and increased production of reactive oxygen species (ROS). ROS mutate genes involved in various metabolic pathways throughout the body and prevent the detoxification and excretion of toxic waste. 

Pancreatic Dysfunction and Damage 

In the pancreas, Hcy can affect insulin and glucagon, leading to higher blood sugar, fat storage, and inflammation. This raises the risk of conditions like diabetes, atherosclerosis, and polycystic ovarian syndrome (PCOS). Symptoms of pancreatic issues include abdominal pain, weight gain, and digestive problems.

Kidney Dysfunction and Disease

High Hcy levels also impact the kidneys by breaking down glutathione, which harms kidney function. This can cause pain, swelling, and other kidney issues.

Bone Issues

In bones, high Hcy reduces blood flow, lowers bone mineral density, and increases the risk of osteoporosis and fractures. In the eyes, it can lead to retinopathy, optic nerve damage, and glaucoma by reducing blood flow and triggering inflammation.

Eye Issues  

High homocysteine (Hcy) levels are linked to eye problems like retinopathy, optic nerve damage, and glaucoma. Hcy causes oxidative stress, reducing blood flow to the eyes and damaging eye cells, leading to inflammation, nerve damage, and faster cell death.

Brain and Nervous System Dysfunction and Damage

High Hcy levels interfere with SAMe and DNA methylation, affecting brain function. Hcy harms brain pathways and reduces important chemicals like serotonin, increasing the risk of brain damage and mental health issues.

 

 

Figure 10: High homocysteine (HHcy) levels can damage multiple organs by producing toxic byproducts from cysteine and methionine. One common effect of HHcy is postural tachycardia syndrome (PoTS), which causes heart issues in people of all ages. PoTS is responsible for about 32.2% of fainting cases in children.

 

Cancer

Hcy competes with SAMe, affecting DNA methylation and harming brain function, which can lead to mental health and nervous system disorders. It also lowers glutathione levels, increasing oxidative stress and promoting cancer cell growth.

Figure 11: Platelets and tumor cells modulate the immune response and increase the production of proinflammatory proteins (like cytokines) and reactive oxygen species [inflammation] (1 and 2). Tumor cells induce platelet aggregation 64 (3) and support angiogenesis (new blood vessel formation) (4). Natural killer (NK) cells are prevented from ingesting and destroying tumor cells, pathogens, and other foreign invaders in circulation(5)54. Instead, neutrophils focus on assisting the stabilization and integrity of the blood vessel (2)64 and shielding tumor cells from destruction . Thus, the cytokines released from these reactions promote tumor growth, migration, and invasion into blood vessels (6) .

 

Adverse Pregnancy Outcomes

During pregnancy, high Hcy can cause complications like high blood pressure (e.g., preeclampsia), repeated miscarriages, birth defects, and premature birth. It can also affect hormone levels, kidney function, and glucose metabolism.

 

Figure 12: High homocysteine levels can lead to pregnancy problems by affecting enzymes and blood flow to the placenta. Vitamin deficiencies, DNA changes, and blood vessel damage harm the placenta, raising the risk of high blood pressure, preeclampsia, and other complications for mother and baby.

 

Clinical Significance of Low Homocysteine Levels

Low homocysteine (Hcy) levels usually indicate good health and enough vitamins B6, B9, and B12 from a balanced, plant-based diet. These vitamins help control Hcy levels. Low methionine intake (from animal products, nuts, and some legumes) or excess folate, B6, betaine, or N-acetylcysteine supplements can lower Hcy. During pregnancy, higher albumin levels can also reduce Hcy.

Hcy stores cysteine, which is needed to make glutathione (GSH), an important antioxidant. Too much methionine can lower both Hcy and GSH, leading to more free radicals and damage to DNA, RNA, and mitochondria. Mutations in the CBS gene can cause disorders like Down’s syndrome and peripheral neuropathy.

Figure 13: Dietary methionine increases the conversion of homocysteine (Hcy) to cysteine and, further to glutathione (GSH), resulting in low blood Hcy levels. GSH neutralizes free radicals, keeps oxidative stress under control, and prevents all-cause morbidity and mortality. Excess and chronic consumption of methionine-rich meals overutilizes this metabolic pathway, resulting in excess reactive oxygen species (ROS) production. ROS damages the genetic code of the enzymes involved in transmethylation and transsulfuration and increases the degradation of GSH and the free radical hydrogen sulfide (H2S) produced. 

Prevalence and Statistics of Abnormal Homocysteine Levels 

Both high and low homocysteine (Hcy) levels can signal health issues, particularly heart disease. High levels (over 15 micromol/L) and low levels (below 5 micromol/L) are affected by factors like diet, exercise, medications, age, sex, and health. For example, a larger waistline increases the risk of high Hcy by 5%, and smoking raises the risk by 24%. Eating fewer fruits and vegetables also increases the risk. A 5 μmol/L increase in Hcy raises the chance of early death by 33.6%.

High Hcy is often linked to low levels of vitamins B6, B9, and B12 and affects about 5% of people, with higher risks in those with poor diets, older adults, men, and people in low-income countries. In places like Ethiopia, high Hcy is linked to high blood pressure due to limited access to fresh produce. In India, 93% of men and 81% of women are affected.

Genetics can also cause high Hcy, with a common mutation in the MTHFR gene increasing the risk of heart disease and blood clots. Around 20-40% of white or Hispanic people carry this mutation, which reduces enzyme function by 35%. In some regions, 8-20% of people have a more severe form, reducing enzyme activity to just 30%.

 

Conclusion

Homocysteine (Hcy) is an important marker for checking metabolic health. High Hcy levels are often caused by low intake or poor metabolism of vitamins B6, B9, and B12 (found in green vegetables and citrus) or by gene mutations that affect Hcy breakdown. Low Hcy levels generally signal good health and proper metabolism in the body. Very low Hcy can happen with too much B vitamin supplementation or during pregnancy.

Tracking Hcy levels in lab tests can provide important information about a person’s risk for diseases and overall health. A healthy lifestyle with a balanced plant-based diet, staying hydrated, and regular exercise helps control Hcy levels and can reduce side effects from medications used for chronic conditions like diabetes, heart disease, and cancer. Research on how genetics, lifestyle, and diet affect Hcy metabolism can improve our understanding of how to prevent and manage chronic health issues.

 

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