Homocysteine (Hcy)

    Homocysteine (Hcy) is not a classic amino acid found in dietary protein. Homocysteine’s only source in humans is the demethylation of s-adenosylmethionine (SAM).

    Homocysteine is a major branch point in the methylation pathway. It can be metabolized via two pathways: degraded irreversibly through the transsulfuration pathway or re-methylated back to methionine. These two pathways are greatly affected by vitamin and mineral cofactor availability and enzymatic SNPs.

    Transsulfuration is the main route for irreversible Hcy disposal. Transsulfuration begins when Hcy is converted to cystathionine, using the cystathionine β-synthase enzyme (CBS). This reaction requires nutrient cofactors, such as vitamin B₆ and iron.

    Alternatively, Hcy can be re-methylated back to methionine.61 Two distinct routes exist for Hcy remethylation. The first reaction is dependent on folate and vitamin B₁₂. The second route for Hcy remethylation is independent of folate, but requires betaine. The betaine pathway for Hcy remethylation is a salvage pathway when folate metabolism abnormalities are present or in folate deficiency.8 Under normal conditions, the body will remethylate Hcy several times before allowing irreversible transsulfuration.

    Whereas SAM-dependent methylation occurs in nearly all tissues, the transsulfuration pathway and Hcy remethylation occur primarily in the liver and kidneys.

    Hcy intracellular concentration is under tight control. As mentioned above, SAH accumulation must be avoided as it can inhibit all methylation reactions. Because of AHCY’s reversible nature, it is mandatory that intracellular Hcy concentrations are kept within strict limits. Optimal Hcy concentrations in cells are maintained or re-established through folate-dependent remethylation. Whenever the cellular capacity to metabolize Hcy is exceeded, this amino acid will be exported to the extracellular space until intracellular levels are normalized. This results in elevated plasma Hcy levels. Exceptions are liver and kidney cells, where Hcy can enter the transsulfuration pathway.

    As alluded to above, several factors can affect Hcy metabolism causing hyperhomocysteinemia. These include B-vitamin deficiencies, impaired renal excretion, advanced age, sex (male), smoking, alcohol, and genetic enzyme deficiencies.

    Elevated homocysteine levels have many clinical implications.

    Hyperhomocysteinemia is regarded as a risk factor for non-coronary atherosclerosis and coronary artery disease. Elevated homocysteine enhances vascular smooth-muscle cell proliferation, increases platelet aggregation, and acts on the coagulation cascade and fibrinolysis, causing normal endothelium to become more thrombotic. The mechanism may be related to elevations in SAH, due to the reversible nature of Hcy formation. SAH has been shown to be a more sensitive marker in many diseases as previously outlined.

    Diabetes, both type 1 and type 2, initially causes hypohomocysteinemia, due to renal hyperperfusion early in the diabetic nephropathy disease process. This progresses to hyperhomocysteinemia as renal function becomes compromised.

    Elevated homocysteine levels have also been implicated in gastrointestinal disorders such as inflammatory bowel disease and colon cancer.61,65 Hyperhomocysteinemia may be partially due to nutrient malabsorption (methyl donor and B-vitamin deficiency). Subsequently, elevated Hcy has been shown to induce inflammatory cytokines and contribute to disease progression.

LOW HOMOCYSTEINE

• Unknown clinical significance

• May be a sign of over-methylation, though literature not available

• CBS SNP in the presence of oxidative stress or inflammation

• AHCY deficiency (lack of vitamin B3)

HIGH HOMOCYSTEINE

• Vitamin B6 or iron deficiency (CBS enzyme cofactors)

• Enzymatic deficiency in MTR/MTRR/BHMT

• Folate deficiency with low choline intake

• Alcohol

• Tobacco