Hyperhomocysteinemia

Homocysteine arises from dietary methionine. High levels of homocysteiae (hyperhomocysteinemia) are a risk factor for occlusive vascular diseases including atherosclerosis and thrombosis (81—84). In a controlled study, semm folate concentrations of <9.2 nmol/L were linked with elevated levels of plasma homocysteiae. Elevated homocysteine levels have beea associated also with ischemic stroke (9). The mechanism by which high levels of homocysteine produce vascular damage are, as of yet, aot completely uaderstood. lateractioa of homocysteiae with platelets or eadothehal cells has beea proposed as a possible mechanism. Clinically, homocysteine levels can be lowered by administration of vitamin B, vitamin B 2> foHc acid. 

Folic Acid Supplements Reduce the Risk of Neural Tube Defects Hyperhomocysteinemia... 

Supplements of 400 Ig/d of folate begun before conception result in a significant reduction in the incidence of neural mbe defects as found in spina bifida. Elevated blood homocysteine is an associated risk factor for atherosclerosis, thrombosis, and hypertension. The condition is due to impaired abihty to form methyl-tetrahydrofolate by methylene-tetrahydrofolate reductase, causing functional folate deficiency and resulting in failure to remethylate homocysteine to methionine. People with the causative abnormal variant of methylene-tetrahydrofolate reductase do not develop hyperhomocysteinemia if they have a relatively high intake of folate, but it is not yet known whether this affects the incidence of cardiovascular disease. 

Growing clinical data also points to the importance of IL-8 in atherogenesis. IL-8 has been found in atheromatous lesions from patients with atherosclerotic disease including carotid artery stenosis (103), CAD (118), abdominal aortic aneurysms (AAA) (103,104,114), and peripheral vascular disease (PVD) (104). Furthermore, studies using plaque explant samples have yielded more direct evidence for IL-8 involvement. Media from cultured AAA tissue induced IL-8-dependent human aortic endothelial cell (HAEC) chemotaxis (122). Homocysteine, implicated as a possible biomarker for CAD, is also capable of inducing IL-8 (123-125) by direct stimulation of endothelial cells (123,124) and monocytes (125). When patients with hyperhomocysteinemia were treated with low-dose folic acid, decreases in homocysteine levels correlated with decreases in IL-8 levels (126). Statins significantly decrease serum levels of IL-6, IL-8, and MCP-1, as well as expression of IL-6, IL-8, and MCP-1 mRNA by peripheral blood monocytes and HUVECs (127). Thus, IL-8 may be an underappreciated factor in the pathogenesis of atherosclerosis. 

Sun W, Wang G, Zhang ZM, Zeng XK, Wang X. Chemokine RANTES is upregu-lated in monocytes from patients with hyperhomocysteinemia. Acta Pharmacol Sin 2005 26(11) 1317—1321. 

Hyperdispersants, 3 677 Hyperfiltration, 25 890 Hyperglycemia, as cause of age-related conditions, 2 813 Hyperhomocysteinemia, 2 822... 

Homocyst(e)ine CBS deficiency Cobalamin defects/defi-ciency MTHFR deficiency Methionine adenosyltrans-ferase deficiency Hyperhomocysteinemia Sulfite oxidase deficiency... 

Goldstein, M. Leibovitch, I., Yeffimov, I., Gavendom, S., Sela, B.A., and A. Loewenstein, 2004, Hyperhomocysteinemia in patients with diabetes mellitus with and without diabetic retinopathy. Eye 18, 460-465. 

As shown in the review of the homocysteine metabolism, vitamin B 2, vitamin B6, and folate are important cofactors in the metabolic pathways for homocysteine elimination, and consequently, deficiencies of these vitamins are characterized by elevated plasma concentrations of tHcy. Hyperhomocysteinemia is also frequently found in diseases such as renal failure, rheumatic and auto-immune diseases, hypothyroidism, and malignancies. Several drugs are also known to increase plasma tHcy concentrations (16-24). 

Many studies published during the last few decades have suggested that hyperhomocysteinemia is a risk factor for coronary artery disease (CAD), stroke, and thromboembolic disease. The Homocysteine Studies Collaboration metaanalysis of 30 studies concluded that elevated tHcy is a moderate risk factor for ischemic heart disease a level 3 xmol/L lower reduces the risk with an odds ratio of 0.89 (95% Cl = 0.83-0.96). The same was true for homocysteine as a risk factor for stroke (odds ratio = 0.81 95%5CI = 0.69-0.95) (6). A meta-analysis of 40 studies of the MTHFR 677 C > T polymorphism demonstrated a mildly increased risk of coronary heart disease with an odds ratio of 1. 16 (95% Cl = 1.05-1.28) (25). 

In vitro studies have shown that homocysteine can undergo autoxidation, leading to the formation of oxygen free radicals (30-32). Homocysteine is involved in oxidative modification of low-density lipoprotein in vitro (33). Increased lipid peroxidation in humans with hyperhomocysteinemia has been reported (34,35). However, vitamin supplementation that resulted in substantial reduction of tHcy concentrations did not normalize either the homocysteine redox status or the increased lipid peroxidation in CAD patients (35,36). 

Homocysteine decreases the bioavailability of nitrous oxide (NO) via a mechanism involving glutathione peroxidase (37). Tawakol et al. (38) reported that hyperhomocysteinemia is associated with impaired endothelium-dependent vasodilation in humans. Homocysteine impairs the NO synthase pathway both in cell culture (39) and in monkeys with hyperhomocysteinemia, by increasing the levels of asymmetric dimethylarginine (ADMA), an endogenous NO synthase inhibitor (40). Elevation of ADMA may mediate endothelial dysfunction during experimental hyperhomocysteinemia in humans (41). However, Jonasson et al. (42) did not find increased ADMA levels in patients with coronary heart disease and hyperhomocysteinemia, nor did vitamin supplementation have any effect on ADMA levels in spite of substantial plasma tHcy reduction,... 

Epidemiological studies indicate that elevated plasma tHcy increases the risk of venous thromboembolism (43,44), In homocystinuria, the presence of the factor V Leiden mutation further increases the risk of thromboembolism (45). It has been proposed that hyperhomocysteinemia might interfere with the inhibition of activated factor V by activated protein C, possibly via similar effects as those caused by the factor V Leiden mutation (46,47), However, one in vitro study (48) and one large clinical study failed to demonstrate an association between hyperhomocysteinemia and activated protein C resistance (49). 

Increases in plasma S-AA levels have previously been reported in patients with coronary disease (57). S-AA and plasma intracellular adhesion molecule-1 were elevated in patients with CAD and hyperhomocysteinemia, but only S-AA decreased after vitamin supplementation (35). Homocysteine activates nuclear factor- in endothelial cells, possibly via oxidative stress (58), and increases monocyte chemoattractant protein-1 expression in vascular smooth muscle cells (59). Additionally, it stimulates interleukin-8 expression in human endothelial cultures (60). These inflammatory factors are known to participate in the development of atherosclerosis. Taken together, these reports suggest an association of elevated tHcy and low-grade inflammation in CAD. 

To conclude, hyperhomocysteinemia is associated with oxidative stress, inflammation, endothelial dysfunction, and dysfunction of coagulation in animals and in humans, but vitamin supplementation does not consistently normalize these changes in spite of large reductions in homocysteine. It still remains be seen whether homocysteine per se causes the pathological processes or whether it is simply an innocent bystander. 

Morgan SL, et al. Folic acid supplementation prevents deficient blood folate levels and hyperhomocysteinemia during longterm,low dose methotrexate therapy for rheumatoid arthritis implications for cardiovascular disease prevention. J Rheumatol 1998 25(3) 44l-446. 

Cattaneo M, Martinelli I, Mannucci PM, Hyperhomocysteinemia as a risk factor for deep-vein thrombosis. N Engl J Med I 996 335(13) 974-975 author reply 975-976. 

Sauls DL, Wolberg AS, Hoffman M. Elevated plasma homocysteine leads to alterations in fibrin clot structure and stability implications for the mechanism of thrombosis in hyperhomocysteinemia. J Thromb Haemost 2003 l(2) 300-306. 

AuTfeung KK, et al. Hyperhomocysteinemia activates nuclear factor-kappa B in endothelial cells via oxidative stress. Circ Res 2004 94(l) 28-36. 

Cardiac Gas and Gai Modulate Sympathetic Versus Parasympathetic Mechanisms in Hyperhomocysteinemia... 

Load creates hyperhomocysteinemia (HHcy) The chronic pressure or volume overload by hypertension, aortic stenosis, and aortic vena cava fistula increases Hey by volume retention, in addition, by decreasing the activities of MTHFR, MS, CBS, and CGL enzymes (Figure 3.3). During load Hey chelates the Cu2+ in CytC, Cox,... 

Naruszewicz M, et al. 2006. Hyperhomocysteinemia in patients with symptomatic chronic heart failure Prevalence and prognostic importance - pilot study. Atherosclerosis doi 10.1016/j.atherosclerosis.2006.08.014. 

Rosenberger D, Moshal K, Kartha G, et al. 2006. Arrhythmia and neuronal/endothelial myocyte uncoupling in hyperhomocysteinemia. Arch Physiol Biochem 112 219-227. 

T. Tamura, S. M. Bergman, and S. L. Morgan, Hyperhomocysteinemia as a cause of vascular occlusion in end-stage-renal disease, Int. J. Artificial Organs. 21, 72-74 (1998). 

He was diagnosed with moderate hyperhomocysteinemia and treated with 2.0 mg folic acid daily. He continued to take warfarin and clopidogrel. After 1 month, his plasma total homocysteine level had decreased to 9 pmol/L. He had no further episodes of weakness or other neurological symptoms during the ensuing 12 months. 

Mild hyperhomocysteinemia is defined as a plasma tHcy concentration of 10-30 (tmol/L moderate hyperhomocysteinemia is classified as 30-100 tmol/L. A very severe form of hyperhomocysteinemia, which produces plasma tHcy concentrations greater than 100 tmol/L, can be caused by one of several inborn errors of methionine metabolism. Patients with these disorders also have high levels of tHcy in their urine, a condition known as homocystinuria. 

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