October, 2011

VOL 1 ISSUE 3

CHRONICLES IN CHOLESTEROL
An Insiders Guide to State of The Art Cardiovascular Prevention Laboratory Testing Available From
Numerous studies suggest Everest Clinical Laboratories that homocysteine may be a modifiable risk factor for cardiovascular disease. In experimental studies, homocysteine causes oxidative stress, damages endothelium, and enhances thrombogenicity. In general, epidemiologic studies show an independent and graded association between homocysteine levels and cardiovascular risk. The observational data suggest that even mild-to-moderate elevations in homocysteine increase cardiovascular risk.. Folic acid is the most important dietary determinant of homocysteine; daily supplementation with 0.5 to 5.0 mg typically lowers plasma homocysteine levels by about 25 percent. Vitamin B12 supplementation of at least 0.4 mg daily further lowers levels by about 7 percent, and vitamin B6 supplements may be particularly important in lowering homocysteine after methionine loading. The problem is that several studies have shown no benefit to lowering homocysteine levels with B vitamins. It is possible that elevated homocysteine levels may be a risk marker for cardiovascular disease and should not necessarily be the target of therapy. In 1969, a connection between homocysteine and cardiovascular disease was proposed when it was observed that people with a rare hereditary condition called homocystinuria are prone to develop severe cardiovascular disease as young adults. In this condition, an enzyme deficiency causes homocysteine to accumulate in the blood and to be excreted in the urine. Abnormal homocysteine elevation also occurs among people whose diet contains inadequate amounts of folic acid, vitamin B6, or vitamin B12. Regardless of the cause of the elevation, supplementation with one or more of these vitamins can lower plasma homocysteine levels. Studies done in the 1980s and 1990s linked elevated blood levels of homocysteine to increased risk of premature coronary artery disease, stroke, and venous blood clots, even among people with normal cholesterol levels. These studies led to speculations that high homocysteine levels could contribute to atherosclerosis in at least three ways: (a) a direct toxic effect that damages the cells lining the inside of the arteries, (b) interference with clotting factors, and (c) oxidation of low-density lipoproteins (LDL). Lowering the serum concentration of homocysteine has been proven to reduce the risk of adverse cardiovascular events among people with homocystinuria. Without clinical trials, however, it was impossible to know whether abnormal homocysteine levels among the general population cause atherosclerosis or are merely a "marker"a non-causative finding that often occurs in people with atherosclerosis.

In This Issue: Homocysteine

Although there is a correlation between cardiovascular disease and elevated homocysteine levels, the necessity for homocysteine lowering treatment is not clear.

October, 2011

VOL 1 ISSUE 3

Lowering Homcysteine Levels

Homocysteine elevation is an independent, modifiable risk factor for cardiovascular disease. It is an intermediate amino acid formed during the metabolism of methionine. Plasma homocysteine is normally 12 mol/L, but when elevated has many deleterious cardiovascular effects. Supplements combining folic acid and vitamins B6 and B12 did not reduce the risk of major cardiovascular events in patients with vascular disease. The HOPE-2 and NORVIT trials showed no reduction in cardiovascular events despite impressive homocysteine lowering with vitamin therapy. It is possible that the mechanism for lowering homocysteine needs to be evaluated in light of negative results associated with B vitamins. The homocysteine concentration in the blood is an important reflection of the status of intracellular methionine metabolism. The metabolic pathway that homocysteine takes can be influenced by alterations in the concentrations of folic acid, vitamin B6, and vitamin B12, and by activities of the various enzymes that participate in metabolic processes.

Homocysteine concentration is influenced by age, gender, and medication and by genetic, nutritional, and pathologic factors. Plasma homocysteine increases with age, possibly due to renal impairment: There is a positive correlation between creatinine levels and plasma homocysteine. In general, men have higher levels of homocysteine than women, most likely due to higher creatinine values and greater muscle mass. Women, before menopause, have lower levels of homocysteine than do postmenopausal women. Use of some medications nitrous taking oxide, oral raises homocysteine (Dilantin), have levels. and lower

Methotrexate, Usually,

phenytoin

carbamazepine (Tegretol) all increase homocysteine levels. women contraceptives homocysteine. The lipid-lowering agents colestipol and niacin, in combination with thiazide diuretics, may raise homocysteine levels. A total plasma homocysteine level of 12 mol/L is considered optimal. A concentration above 15 mol/L is associated with a high risk of occlusive vascular disease. If the homocysteine level is 100 mol/L, the patient should be referred to a geneticist, especially if several members of the same family have hyperhomocysteinemia By Spencer Kroll MD PhD National Lipid Association Board Certified Board of Directors, Northeast Lipid Association