Homocysteine is a sulfur-containing non-protein amino acid that is formed as a result of physiological transformations of an amino acid supplied from food - methionine. The methionine cycle occurs in all cells of the body and involves the transfer of a methyl group from ATP-activated methionine-S-adenosylmethionine (SAM) to other compounds, resulting in the formation of S-adenosylhomocysteine (SAH), homocysteine (Hcy), and finally the remethylation of Hcy to methionine. The transfer of the methyl group is necessary for the formation of neurotransmitters, regulation of DNA expression, physiological transmethylation of proteins, peptides, nucleic acids, and phospholipids. Homocysteine and serine are also substrates for the irreversible transsulfuration reaction, which results in the formation of cystathionine and then cysteine. This process occurs in the liver, kidneys, small intestine, and pancreas. The proper course of the mentioned metabolic pathways is determined by the presence of B-group vitamins as reaction cofactors and folic acid as a methyl group donor in the methionine regeneration proces.

In physiological states, the methionine cycle is regulated by methionine consumption. With balanced intake, it usually occurs about twice, and then homocysteine is used in the transsulfuration pathway. With low intake, the number of cycles increases, while with high methionine intake, the conversion of Hcy to cystathionine becomes the main metabolic pathway.

Hyperhomocysteinaemia (HHcy) is a pathological condition associated with high levels of homocysteine in the human body. The severity of this condition is classified based on the concentration of homocysteine in serum. A concentration of 15-30 µmol/L is considered moderate HHcy, while 30-100 µmol/L is considered moderately severe, and above 100 µmol/L is considered severe. Values around 500 µmol/L are found in patients with a genetically determined disease called homocystinuria.

There are two main types of hyperhomocysteinaemia: primary, resulting from a genetically determined deficiency of enzymes involved in homocysteine metabolism, and secondary hyperhomocysteinaemia, associated with deficiencies in B vitamins and folic acid, kidney and liver failure, diabetes, hypothyroidism, taking certain medications, consuming large amounts of coffee, alcohol, and smoking.

Latent hyperhomocysteinaemia is a condition that can occur in individuals with a mutation in the genes encoding enzymes of the methionine-homocysteine pathway. It is characterized by a significant increase in homocysteine levels in a methionine load test.

Hyperhomocysteinaemia a is a condition of reduced homocysteine level (below 5.0 µmol/L) that occurs in about 0.5-1% of the population. It may result from inadequate methionine intake.

Hyperhomocysteinaemia is an independent risk factor for the development of cardiovascular diseases, including thrombosis and atherosclerosis, ischaemic and haemorrhagic stroke, as well as a prognostic factor for mortality due to coronary artery disease. It is associated, among other things, with the inhibition of endothelial cell proliferation and stimulation of vascular smooth muscle cell formation, decreased vascular wall relaxation capacity, LDL oxidation, foam cell formation, platelet activation, increased release of cytokines, chemokines, and other pro-inflammatory factors. A 25% reduction in homocysteine levels in the blood can reduce the risk of ischaemic heart disease by 11%, stroke by 19%, and significantly reduce the frequency of foetal developmental defects. In patients with cardiovascular insufficiency, homocysteine levels >20 µmol/l were associated with 4.5 times higher mortality than in patients with homocysteine levels <9.0 µmol/l. An increase in homocysteine levels by every 5 µmol/l was estimated to increase the risk of death in patients with cardiovascular insufficiency by 33%. High levels of Hcy have also been associated with the risk of sudden death in diabetic patients.

Hyperhomocysteinaemia interferes with the production of polyunsaturated fatty acids essential for the normal functioning of the central nervous system. Studies show a link between HHcy and the risk of developing Parkinson's disease, Alzheimer's disease, and age-related dementia. Homocysteine activates kinase Cdk5 and inhibits protein phosphatase 2A (PP2A). These enzymes are responsible for the proper phosphorylation/dephosphorylation of tau protein, which is a marker of neurodegenerative diseases.

Studies have also shown that high levels of homocysteine are correlated with low levels of serotonin, which may have a role in the development of depression. Hyperhomocysteinaemia causes damage to blood vessels and may be a cause of migraine episodes.

There is also confirmed association between high levels of homocysteine and folic acid deficiency with infertility and pregnancy complications, including miscarriages, foetal developmental defects (neural tube defects, teratogenic effects), impaired placental circulation, congenital heart defects, as well as an increased risk of maternal peri-partum thrombotic complications.

Homocysteine concentration increases with the progression of various types of cancers - breast, pancreas, colon, lungs, ovaries, and haematological malignancies. This may be related to increased consumption of folic acid by cancer cells. Additionally, elevated levels of homocysteine increase the risk of co-morbid thromboembolism, which is one of the main causes of death in cancer patients.

Abnormal homocysteine levels are also a risk factor for various eye diseases, such as retinopathy, cataracts, optic nerve atrophy, exfoliative glaucoma, and atherosclerosis of the retinal vessels.

Low homocysteine levels are also a pathological condition. A link has been established between low homocysteine levels and peripheral neuropathy. In rare cases, it can lead to impaired glutathione production and increased sensitivity to oxidative stress. To correct homocysteine deficiencies, supplementation with methionine, N-acetylcysteine, and taurine is recommended.

In summary, abnormal homocysteine levels are a marker and risk factor for a wide range of conditions. If you are planning a pregnancy or are at risk for cardiovascular or neurodegenerative diseases, make sure to maintain proper homocysteine levels.

Criculating in blood homocysteine is bound to serum proteins in 80%. 5-10% occurs as disulphide (two Hcy molecules linked by a sulphur bond), 5-10% as mixed disulphide (cysteine and homocysteine linked by a sulphur bond), and 1-2% in free form. Homocysteine testing in the Masdiag Laboratory is based on the determination of total homocysteine concentration in serum, plasma, or dried blood spot.

The test is performed by isotopic dilution, using a high-performance liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) technique. The use of the LC-MS/MS technique offers analytical possibilities not achievable with other techniques. It allows high repeatability and accuracy of measurements.

An additional advantage is the possibility of performing the test from different materials: serum, plasma, or dried blood spot.

Masdiag Laboratory participates in the international proficiency testing programme - Quality assurance in laboratory testing for IEM (ERNDIM)

• „Homocysteine”
  The International Journal of Biochemistry & Cell Biology, 2000, 32, 385-389, doi: 10.1016/S1357-2725(99)00138-7  
• „Homoicysteine Metabolism”
  Annual Review of Nutrition, 1999, 19(1), 217-246, doi: 10.1146/annurev.nutr.19.1.217 
• „Homocysteine, B Vitamins, and Cognitive Impairment”
  Annual Review of Nutrition, 2016, 36(1), 211-239, doi: 10.1146/annurev-nutr-071715-050947 
• „The metabolism and significance of homocysteine in nutrition and health”
  Nutrition & Metabolism, 2017, 14(78), doi: 10.1186/s12986-017-0233-z 
• „The homocysteine controversy”
  Journal of Inherited Metabolic Disease, 2011, 34, 93–99, doi: 10.1007/s10545-010-9151-1 
• „Homocysteine – from disease biomarker to disease prevention”
  Journal of Internal Medicine, 2021, 290(4), 826-854 doi: 10.1111/joim.13279 
• „Hyperhomocysteinemia and the role of B vitamins in cancer”
  Radiology and Onkology, 2010, 44(2), 79–85, doi: 10.2478/v10019-010-0022-z
• „Homocysteina”
  D. Gąsiorowska, K. Korzeniowska, A. Jabłecka, Farmacja Współczesna, 2008, 1, 169-175 
• „Podwyższone stężenie homocysteiny we krwi jako wskaźnik zagrożenia zdrowia”
  S. Kraczkowska, Z. Suchecka, J. Pachecka, BIULETYN Wydziału Farmaceutycznego Akademii Medycznej w Warszawie, 2005 
• „Homocysteine metabolism as the target for predictive medical approach, disease prevention, prognosis, and treatments tailored to the person”
  EPMA Journal, 2021, 12, 477–505, doi: 10.1007/s13167-021-00263-0