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From: Homocysteine and reactive oxygen species in metabolic syndrome, type 2 diabetes mellitus, and atheroscleropathy: The pleiotropic effects of folate supplementation

1. Age and Gender: HHcy is associated with aging and male gender. Females typically have Hcy levels 20% lower than men until menopause. After menopause fasting levels of Hcy rise to those of men of similar age.
2. Genetic: Not only deficiency but also dysfunction secondary to various gene polymorphisms. 1. Cystathionine Beta Synthase deficiency.
2. 5,10-methylenetetrahydrofolate reductase deficiency.
3. Methionine synthase deficiency (including abnormalities in cobalamin metabolism).
4. Methylenetetrahydrofolate homocysteine methyltransferase deficiency.
3. Renal Function: Hcy levels increase with elevations of creatinine levels. Due to impaired renal excretion (decreased glomerular filtration rate) and or impaired metabolism.
4. Nutritional Status: Decreased vitamin cofactors (folate, vitamin B12, and B6). Aging – Alterations in gastric mucosa affecting intrinsic factor, inflammatory bowel diseases such as Crohn's disease and Ulcerative colitis, celiac disease, lymphomas and amyloidosis to name a few.
5. Disease States: Hypothyroidism. Carcinomas (breast, ovary, and pancreas in particular). Chronic renal failure from any cause especially diabetic and hypertensive nephropathy. Systemic lupus erythematous. Psoriasis. Solid organ transplantation. Malabsorption syndromes associated with nutritional status: Number 4.
6. Medications: Anticonvulsants, such as phenytonin, Methotrexate, Theophylline and other bronchodilaors of the phosphodiesterase inhibitor class, which interfere with pyridoxal phosphate synthesis. Nitrous oxide, L-dopa, Carbamazepine, Niacin, Fibrates, and Bile acid resins to name a few.
7. Endothelial Cell Dysfunction: Any cause for a decrease in eNOS enzyme or eNO bioavailability. Any cause of endothelial cell dysfunction could result in HHcy if one accepts the endogenous endothelial folate shuttle HYPOTHESIS.