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Hyperhomocysteinemia: causes, symptoms, diagnosis, treatment
Medical expert of the article
Last reviewed: 04.07.2025
Hyperhomocysteinemia is a multifactorial process involving genetic and non-genetic mechanisms.
Causes hyperhomocysteinemia
Causes of hyperhomocysteinemia can be hereditary and acquired. Hereditary factors can be divided into enzyme deficiency and transport deficiency.
Pathogenesis
Hyperhomocysteinemia may predispose to arterial or venous thromboembolism, possibly due to damage to the endothelial cells of the vessel wall. Plasma homocysteine levels are increased more than 10-fold in homozygotes with cystathionine synthase deficiency. Less pronounced activation is seen in heterozygous deficiency and in other abnormalities of folate metabolism, including methyltetrahydrofolate reductase deficiency. However, the most common cause of hyperhomocysteinemia is acquired deficiency of folate, vitamin B 12.
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Homocysteine is formed from methionine by transmethylene reactions. The key enzymes in the metabolic pathway of homocysteine conversion are cystothionine beta-synthetase and methylenetetrahydrofolate reductase (MTHFR) in the presence of cofactors - pyridoxine and cyanocobalamin and, as a substrate, folic acid. As a result of gene mutation, the activity of these enzymes decreases and the metabolic pathway of homocysteine conversion is disrupted, and its content in plasma increases.
Decreased dietary intake of pyridoxine, cyanocobalamin, and folate causes hyperhomocysteinemia not only in homozygous carriers but also in people without the MTHFR gene mutation.
The normal plasma homocysteine level is 5–16 μmol/l. An increase in homocysteine levels to 100 μmol/l is accompanied by homocystinuria.
Hyperhomocysteinemia and defects in the development of the central nervous system of the embryo are well studied and explain how and why treatment with folic acid can reduce their occurrence. Hyperhomocysteinemia is associated with such obstetric pathologies as habitual early pregnancy losses, early onset of gestosis, placental abruption, intrauterine growth retardation. At the same time, I. Martinelli et al. (2000) did not find a connection between late fetal death and hyperhomocysteinemia.
It is believed that hyperhomocysteinemia may cause endothelial damage due to impaired redox reactions, increased levels of free radicals, and decreased levels of nitric oxide through effects on the activation of coagulation factors (tissue factor and factor XII) and/or coagulation inhibitors.
Diagnostics hyperhomocysteinemia
Diagnosis is made by measuring plasma homocysteine levels.
Treatment hyperhomocysteinemia
Homocysteine levels can be normalized by dietary interventions with folic acid, vitamin B12, or B (pyridoxine) in combination or monotherapy. However, it is unclear whether this therapy reduces the risk of arterial or venous thrombosis.