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Overview of homocysteine

Robert S Rosenson, MD
David S Kang, MD, PhD
Section Editor
Mason W Freeman, MD
Deputy Editor
Brian C Downey, MD, FACC


Homocysteine is an intermediary amino acid formed by the conversion of methionine to cysteine. Homocystinuria or severe hyperhomocysteinemia is a rare autosomal recessive disorder characterized by severe elevations in plasma and urine homocysteine concentrations. Clinical manifestations of homocystinuria include developmental delay, osteoporosis, ocular abnormalities, thromboembolic disease, and severe premature atherosclerosis. Homocystinuria is not discussed further in this topic review.

Less marked elevations in plasma homocysteine are much more common, occurring in 5 to 7 percent of the population [1,2]. Although unassociated with the clinical stigmata of homocystinuria, mounting evidence suggests that moderate hyperhomocysteinemia is an independent risk factor for atherosclerotic vascular disease and for recurrent venous thromboembolism.

This topic will review the risks associated with elevated homocysteine levels, screening for hyperhomocysteinemia, and the evidence evaluating the use of vitamin supplements that lower homocysteine levels.


Homocysteine is metabolized by one of two divergent pathways: transsulfuration and remethylation (figure 1). The transsulfuration of homocysteine to cysteine is catalyzed by cystathionine-ß-synthase, a process that requires pyridoxal phosphate (vitamin B6) as a cofactor. Remethylation of homocysteine produces methionine. This reaction is catalyzed either by methionine synthase or by betaine-homocysteine methyltransferase. Vitamin B12 (cobalamin) is the precursor of methylcobalamin, which is the cofactor for methionine synthase.

Elevations in the plasma homocysteine concentration can occur due to genetic defects in the enzymes involved in homocysteine metabolism, to nutritional deficiencies in vitamin cofactors, or to other factors including some chronic medical conditions and drugs (figure 1) [3-9]. Some drugs used in the treatment of hypercholesterolemia, such as fibrates and nicotinic acid, can raise homocysteine levels by approximately 30 percent; however, the clinical significance of this is uncertain [10-12]. Cigarette smoking also may elevate homocysteine levels [13]. Chronic kidney failure can increase homocysteine levels due to decreased renal removal and impaired metabolism. (See "Secondary prevention of cardiovascular disease in end-stage renal disease (dialysis)", section on 'Hyperhomocysteinemia'.)


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