hyperhomocysteinemia

Hyperhomocysteinemia is a condition characterized by elevated levels of the amino acid homocysteine in the blood, typically defined as fasting plasma homocysteine above 15 micromoles per liter. It can arise from inherited defects in enzymes of methionine metabolism or from acquired factors that impair remethylation or transsulfuration.

Genetic causes include defects in cystathionine beta-synthase (the enzyme deficient in classic homocystinuria) as well as rarer defects in methionine synthase or in the MTHFR pathway. Acquired causes include deficiencies of folate, vitamin B12, or vitamin B6; chronic kidney disease; hypothyroidism; and certain medications (for example, methotrexate or some anticonvulsants). Lifestyle factors such as smoking and heavy alcohol use, as well as pregnancy, can also influence homocysteine levels.

Pathophysiology and clinical significance: Elevated homocysteine is linked with endothelial dysfunction, oxidative stress, inflammation, and a prothrombotic state, which may contribute to arterial and venous thromboembolism and cardiovascular disease. In inherited forms, there can be more pronounced risk, including thrombotic events and, in childhood, multisystem manifestations such as lens dislocation or skeletal findings. In the general population, elevated homocysteine is considered a risk marker, and the extent to which lowering it reduces cardiovascular events remains a subject of study.

Diagnosis and management: Diagnosis relies on measuring fasting plasma homocysteine, with consideration of renal function and micronutrient status (folate, B12, B6). Management focuses on correcting nutritional deficiencies and addressing underlying causes. Vitamin supplementation with folate, B12, and B6 can reduce homocysteine levels in many individuals. In classic homocystinuria, treatment may include high-dose B6 for responsive patients, betaine to remethylate homocysteine to methionine, and dietary methionine restriction, along with regular monitoring for thrombotic risk.