DACH-LIGA Homocystein (German, Austrian and Swiss Homocysteine Society): Consensus Paper on the Rational Clinical Use of Homocysteine, Folic Acid and B-Vitamins in Cardiovascular and Thrombotic Diseases: Guidelines and Recommendations

Abstract

About half of all deaths are due to cardiovascular disease and its complications. The economic burden on society and the healthcare system from cardiovascular disability, complications, and treatments is huge and getting larger in the rapidly aging populations of developed countries. As conventional risk factors fail to account for part of the cases, homocysteine, a "new" risk factor, is being viewed with mounting interest. Homocysteine is a sulfur-containing intermediate product in the normal metabolism of methionine, an essential amino acid. Folic acid, vitamin B12, and vitamin B6 deficiencies and reduced enzyme activities inhibit the breakdown of homocysteine, thus increasing the intracellular homocysteine concentration. Numerous retrospective and prospective studies have consistently found an independent relationship between mild hyperhomocysteinemia and cardiovascular disease or all-cause mortality. Starting at a plasma homocysteine concentration of approximately 10 micromol/l, the risk increase follows a linear dose-response relationship with no specific threshold level. Hyperhomocysteinemia as an independent risk factor for cardiovascular disease is thought to be responsible for about 10% of total risk. Elevated plasma homocysteine levels (>12 micromol/l; moderate hyperhomocysteinemia) are considered cytotoxic and are found in 5 to 10% of the general population and in up to 40% of patients with vascular disease. Additional risk factors (smoking, arterial hypertension, diabetes, and hyperlipidemia) may additively or, by interacting with homocysteine, synergistically (and hence over-proportionally) increase overall risk. Hyperhomocysteinemia is associated with alterations in vascular morphology, loss of endothelial anti-thrombotic function, and induction of a procoagulant environment. Most known forms of damage or injury are due to homocysteine-mediated oxidative stress. Especially when acting as direct or indirect antagonists of cofactors and enzyme activities, numerous agents, drugs, diseases, and lifestyle factors have an impact on homocysteine metabolism. Folic acid deficiency is considered the most common cause of hyperhomocysteinemia. An adequate intake of at least 400 microg of folate per day is difficult to maintain even with a balanced diet, and high-risk groups often find it impossible to meet these folate requirements. Based on the available evidence, there is an increasing call for the diagnosis and treatment of elevated homocysteine levels in high-risk individuals in general and patients with manifest vascular disease in particular. Subjects of both populations should first have a baseline homocysteine assay. Except where manifestations are already present, intervention, if any, should be guided by the severity of hyperhomocysteinemia. Consistent with other working parties and consensus groups, we recommend a target plasma homocysteine level of <10 micromol/l. Based on various calculation models, reduction of elevated plasma homocysteine concentrations may theoretically prevent up to 25% of card...

Prevalences of hyperhomocysteinemia, unfavorable cholesterol profile and hypertension in European populations

“…Nowadays, treatment is based on the total risk profile of a person (including sex, age, total, HDL and LDL cholesterol, blood pressure, diabetes, smoking and family history or premature CVD) and is focused on 'desirable' levels of CVD risk factors rather than cutoff values for increased levels. Using recent guidelines for a desirable tHcy concentration (o10-12 mmol/ l; Malinow et al, 1999;Graham et al, 1997;Stanger et al, 2003), blood pressure (diastolic blood pressure o90 mmHg and systolic blood pressure o140 mmHg; Kjeldsen et al, 2002) and cholesterol profile (total/HDL ratior5; ATP III, 2001) will identify more subjects that may benefit from treatment that lowers their CVD risk factor levels.…”

Homocysteine Measurement by an Enzymatic Method and Potential Role of Homocysteine as a Biomarker in Dogs

“…"content-markup(./author-grp [1]/aff|./author-grp [1]/dept-list)> Homocysteine (Hcy) is a sulfur-containing intermediate product of methionine metabolism and is further metabolized by vitamin B 12 -or B 6 -dependent pathways. 17 In humans, hyperhomocysteinemia (HHcy) is a sensitive marker of folate and B-vitamin deficiency and is considered an independent risk factor for cardiovascular disease (CVD) and thrombotic-, neurodegenerative-, and Dpregnancy-associated diseases. 13,17 Specifically, HHcy is associated with an increased incidence of congestive heart failure (CHF), as well as with the severity of the disease.…”

“…17 In humans, hyperhomocysteinemia (HHcy) is a sensitive marker of folate and B-vitamin deficiency and is considered an independent risk factor for cardiovascular disease (CVD) and thrombotic-, neurodegenerative-, and Dpregnancy-associated diseases. 13,17 Specifically, HHcy is associated with an increased incidence of congestive heart failure (CHF), as well as with the severity of the disease. In high-risk populations, increased Hcy is a prognostic marker for an increased risk of new CVD events or mortality.…”

Maternal and umbilical homocysteine in preeclampsia

“…Hyperhomocysteinemia results in the loss of endothelial antithrombin function and induction of a procoagulant setting (9,12). The pathogenetic action of homocysteine also includes interference with the nitric oxide (NO) system (homocysteine reduces NO bioavailability by interfering with its synthesis), activation of transcrip- (13,14). The aims of the study were to assess the association between elevated homocysteine levels and development of preeclampsia; to determine homocysteine levels in fetal circulation; to differentiate homocysteine levels in mild and severe preeclampsia; and to compare homocysteine levels in pregnant women with preeclampsia with homocysteine levels measured in the same group of women six months after delivery.…”

“…tion factors stimulating gene expression (activation of sterol-regulatory element-binding protein (SREBP) and protein kinase C (PKC), lipid biosynthesis), chemotaxis and leukocyte adhesion (sICAM-1, VCAM-1, interleukin-8, von Willebrand's factor) (13,14).…”