Homocysteine: A Risk Factor Worth
As an emerging independent risk factor for cardiovascular disease and other aging diseases such as Alzheimer's, homocysteine related research has generated a vast amount of literature and sparked a vigorous debate over the past decade. In fact, a comprehensive textbook is now available describing the role of homocysteine in health and disease (3). This review will survey the history of homocysteine research, the rationale for considering homocysteine as a causative agent, rather than just a marker for vascular diseases; and review the intervention trials for lowering homocysteine in patients.
Homocysteine is a sulfur amino acid and a normal intermediate in methionine metabolism. When excess homocysteine is made and not readily converted into methionine or cysteine, it is excreted out of the tightly regulated cell environment into the blood. It is the role of the liver and kidney to remove excess homocysteine from the blood. In many individuals with in-born errors of homocysteine metabolism, kidney or liver disease, nutrient deficiencies or concomitant ingestion of certain pharmaceuticals, homocysteine levels can rise beyond normal levels and lead to adverse health outcomes. The role of elevated blood homocysteine levels in clinical practice is still being debated. The central question is whether it is clinically beneficial to measure for and treat elevated levels of homocysteine (1-2). While some consider homocysteine as simply a marker but not a treatable causative agent, or ignore homocysteine as an innocuous metabolite that is coincidental to other treatable risk factors; the weight of the scientific evidence suggests otherwise.
In the early 1960's several inborn errors of homocysteine metabolism were described in young children leading to extremely high levels of homocysteine-resulting in mental retardation and early death, caused usually by some cardiovascular event. After examining many cases and performing autopsies on several young people, Kilmer McCully concluded, as did others, that the severely elevated levels of homocysteine were directly responsible for the various vascular lesions in these individuals and he further postulated that moderately elevated homocysteine due to heterozygous mutations in homocysteine related genes or poor vitamin status would also lead to increased risk of cardiovascular disease (4).
By the early 1990's, elevated homocysteine was being considered an independent risk factor for cardiovascular disease (along with cholesterol and other lipid markers, age, gender, smoking status, obesity, hypertension and diabetes). A prospective study of male physicians in 1992 found that acute myocardial infarction (MI) or death due to coronary disease was statistically related to increased homocysteine levels, after adjusting for other risk factors (5). In 1995, a key meta-analysis was published by JAMA in which 27 studies involving over 4,000 subjects concluded that homocysteine was an independent risk factor for cardiovascular disease (CVD) and estimated that 10% of the population's CVD risk is attributable to elevated homocysteine (6). In total there are nearly 100 retrospective and prospective clinical studies linking homocysteine levels and increase risk of cardiovascular outcomes and numerous reviews of the literature available (7-11).
According to a recent meta-analysis of the data, a causal relationship between homocysteine and cardiovascular disease is highly likely (12). The authors conclude that lowering homocysteine 3 µmol/L would reduce the risk of ischemic heart disease by 16%, deep vein thrombosis by 25% and stroke by 24%.
Figure 2 shows the basic metabolic pathways concerning homocysteine. Homocysteine is an intermediate in methionine metabolism, the latter being derived primarily from dietary protein. This pathway involves the formation of S- adenosylmethionine (SAM) which subsequently transfers a methyl group to any number of several methyl acceptor molecules (DNA, proteins, neurotransmitters) and forms adenosylhomocysteine, which is subsequently converted to homocysteine.
Homocysteine is then either converted back to methionine by remethylation or further metabolized to cysteine via the transsulfuration pathway. Remethylation primarily occurs when a methyl group is transferred from methyltetrahydrofolate (MTHF), the active form of the folic acid/folate cycle, by a methyltransferase enzyme requiring cobalamin (vitamin B12) as a necessary cofactor. A secondary remethylation pathway, active primarily in liver and kidney cells, uses trimethylglycine (a.k.a. betaine) as the methyl donor. The transsulfuration pathway requires two enzymatic reactions, both of which require the cofactor pyridoxal-5-phospate- the active form of vitamin B6.
Homocysteine (Hcy) levels can easily be measured in most laboratories which test for other blood chemicals. It is important to follow the instructions provided by the lab to ensure consistent homocysteine measurements. Often, incorrect values are a result of poor collection, poor post-collection procedures (not centrifuging or storing on ice soon enough), or non-fasting conditions. Average fasting plasma total homocysteine for "healthy" subjects in the current folic acid fortified U.S. population is between 6 and 12 µmol/L (or µM). In normal subjects, 75% of total plasma Hcy (tHcy) is bound to various proteins (primarily albumen) via disulfide bonds. The remaining 25% free Hcy is found mostly as oxidized homocysteine dimers (homocystine) or as homocysteine-cysteine heterodimers; while only about 1-2% is in the reduced state. Because of the many forms of homocysteine, tHcy was often termed "Homocyst(e)ine" in the literature to account for these multiple forms. Currently, most of the studies concerning Hcy levels have primarily focused on tHcy levels and not on free Hcy or free/bound ratios. Some advocate for the use of free Hcy as a marker rather than tHcy or even intracellular levels rather than plasma levels, although more research in humans needs to be conducted as other species such as rats have 65-75% of tHcy as free Hcy.
Elevated plasma tHcy is an independent risk factor for cardiovascular as well as non-cardiovascular mortality (31, 13). In a prospective cohort study following 2127 men and 2639 women for over 4 years, increasing levels of plasma tHcy was directly related with increasing mortality. The population was divided into quintiles based on initial plasma tHcy (5.1-8.9, 9.0-11.9, 12.0-14.9, 15.0-19.9, >20 µmol/L) and followed for survival. After adjusting for other cardiovascular risk factors the overall mortality ratio was 1, 1.33, 2.02, 2.48, and 3.56 for the 5 quintiles. The authors conclude that after multivariate adjustment, a 5 µmol/L increase in tHcy increased all cause mortality by 49%, cardiovascular mortality 50%, cancer mortality 26% and non-cancer, non-cardiovascular mortality 104%. This data suggests that the level of homocysteine which is likely to result in a low risk for mortality is below 9 and perhaps even lower. Figure 1 shows a graph of increasing coronary artery disease (CAD) risk (both fatal and non-fatal) summarized from the various prospective trials available. The data suggest that the relative risk surpasses one at 6.5 µmol/L, and continues to increase in a near linear fashion until plasma levels of 20 µmol/L or more.
Increased Acute Coronary Syndromes
Increased Stroke Risk
Risk of Hypertension
Risk of Cognitive Disorders and Dementia
In two separate community studies, increasing serum homocysteine levels was inversely related to how well healthy elderly subjects performed on the Mini-mental State Examination, widely used to measure cognitive impairment in elderly patients (38,39). Of course, mild cognitive impairments is one of the leading risk factors for dementias and specifically Alzheimer" s disease (41).
While the mechanism is not fully understood, many of the same processes may be at work in cerebrovascular tissue and neurons as are proposed for arterial endothelial damage (see section Possible Mechanisms for Homocysteine). Alzheimer patients have higher plasma homocysteine levels, but they also have higher levels of asymmetric dimethylarginine and decreased concentrations of nitric oxide (43), two risk factors for cardiovascular disease related to the oxidative affects of homocysteine and perhaps emerging risk factors for dementia. It is known that patients with either mild cognitive impairments or Alzheimer's disease have similarly and severely reduced levels of all major antioxidants (44). How much homocysteine plays in the reduction of these plasma antioxidants remains to be seen, however in vitro research on oligodendrocytes suggests that homocysteine increases the neuronal cytotoxic effect of amyloid beta-peptides (45). A very recent published report also suggests that a protein called transthyretin (prealbumin) becomes amyloidogenic and potentially a factor in dementia when it is bound to homocysteine (46). Another interesting finding is that treating patients with hyperhomocysteinemia and mild cognitive impairment with folic acid, B6 and B12 improves the function of the blood brain barrier (47).
Homocysteine and Diabetes
Homocysteine and Cancer Risk
Homocysteine and Kidney Disorders (56)
It is important to note that only free (unbound) homocysteine is filtered and metabolized by the kidney. As this represents only 25% of the plasma tHcy levels in humans, one way to increase kidney filtration efficiencies (in patients with normal kidney function) may be to stimulate the conversion of bound Hcy to free Hcy. This has been clinically proven by giving patients N-acetylcysteine (NAC), a thiol compound that directly, or through increased glutathione levels can break homocysteine-protein disulfide bonds. See NAC heading in "Homocysteine Lowering Therapies" section for more details.
Homocysteine and the Risk for Other Conditions
In order to consider homocysteine a causative rather than coincidental factor, plausible mechanisms for homocysteine action must be presented and tested. The most common and plausible mechanism are briefly outlined here.
Relation to Other Risk Factors
Vascular Smooth Muscle Cell Proliferation
We have reviewed the various diseases for which homocysteine is a risk factor or marker and the potential mechanisms by which homocysteine may be a causative factor. Here we will briefly review the factors which predispose or cause elevated homocysteine levels. Table 1 summarized this information.
Diet and Lifestyle Factors
It is obvious from the metabolism of homocysteine (Figure 2) that if the required metabolic cofactors folic acid, vitamin B6 or vitamin B12 are suboptimal in the diet, homocysteine levels may elevate. In fact, hyperhomocysteinemia can be induced in monkeys simply by increasing methionine and decreasing folic acid and choline, the precursor of betaine, from their normal diet (67). Numerous human epidemiological studies have shown homocysteine levels correlate inversely and closely with plasma folate levels and less so with vitamin B12 and B6 levels (68,69,70).
The DASH diet, promoted for lowering hypertension, also significantly lowers homocysteine levels- presumably because it promotes higher intake of fruits and vegetables, providing more folic acid and vitamin B6 and lower amounts of methionine (28). Interestingly, while increasing fruit and vegetable intake seems to lower homocysteine levels (71), strict vegetarians are often at risk for hyperhomocysteinemia due to low plasma B12 levels (72, 73). Coffee consumption (4 cups/day) seems to be linked with moderate elevations in homocysteine (74,75), although this effect can apparently be countered by supplementing with 200mg/day of folic acid (76). Moderate levels of alcohol consumption (even wine) may raise homocysteine levels (77)- although some reports claim that moderate beer consumption may actually lower homocysteine levels (79). As with nearly every other cardiovascular risk factor, smoking cigarettes is linked with elevated levels of homocysteine (80,81).
Genetic Defects in Homocysteine Metabolism
Mutations in the gene encoding for the enzyme methylenetetrahydrofolate reductase (MTHFR) are well known in the literature. This enzyme is responsible for the conversion of 5,10 methylenetetrahydrofolate to 5-methyltetrahydrofolate (MTHF or 5MTHF), the active folate that donates its methyl group to homocysteine to make methionine (Fig. 2 ). Certain rare defects in this gene render the enzyme completely dysfunctional and these individuals are noted for extremely high homocysteine, homocystinuria, brain damage and childhood cardiovascular disease. An extremely common mutation in the MTHFR gene, known as a polymorphism because it occurs at greater than 1% in most populations, results when a cytosine is replaced by a thymine at base pair number 677 (C677T). This polymorphism leads to an alanine to valine change in the enzyme which results in a 55-65% loss in enzyme activity. Individuals with errors in both alleles (TT homozygous) may realize this level of enzyme activity reduction, while those with a C677T change in one allele (CT heterozygous) will have only a 25% loss in activity compared to a CC homozygous individual (85,86). The frequency of this polymorphism is very low in some populations (1% in those of African descent) and very high in others (11-15% in Anglo-Americans and 20% in Italian, Hispanic and Columbians). As half of the homocysteine is metabolized by remethylation to methionine, this polymorphism is often associated with elevated homocysteine levels, although adequate folate levels minimize this significantly (87,88 ). A complete meta-analysis of the C677T polymorphism effect on the risk for heart disease has recently been published (111).
Pharmaceuticals that Increase Homocysteine (3,29,52,89)
If the debate over whether moderate hyperhomocysteinemia is a causative agent for various diseases is relatively convoluted, the treatment that effectively lowers homocysteine levels is, conversely, fairly straight forward.
High Dose Folic Acid
While moderate supplementation of folic acid supplementation is successful in lowering homocysteine in the vast majority of the population, many individuals with cardiovascular disease, kidney disease ( including renal transplant patients or patients on hemodialysis) are refractory to these lower levels and require significantly higher levels of folic acid supplementation (2-15 mg/day are often used ) (115-117). As most of these studies were done in combination with other vitamins, these studies will be discussed in the "Combination Treatments" below. It is interesting to note that nearly all of the large intervention trials currently assessing the role of folic acid (in combination with other vitamins) for the reduction of homocysteine and cardiovascular risk use at least 2mg/day of folic acid. When using these higher doses of folic acid, additional vitamin B12 is usually recommended to prevent a masked B12 deficiency.
Forms of Folic Acid
Vitamin B12 and Vitamin B6
Combination Treatment and Clinical Outcomes
Improved vascular endothelial function was demonstrated by measuring brachial artery flow-mediated dilation in coronary heart disease patients given 5mg folic acid and 1mg vitamin B12 daily for 8 weeks (127). In these patients, tHcy levels went from an average of 13.0 to 9.3 in these 8 weeks, while flow-mediated dilation improved from 2.5% to 4.0% at the same time (placebo-group showed no improvement in either). The authors believe that because flow-mediated dilation is mediated through NO and homocysteine is known to lower NO levels, this is one of the likely mechanisms attributed to this therapy. Additionally, these authors believe it is the reduced unbound form of homocysteine (which accounts for only about 1-2% of the tHcy) that may be the culprit in endothelial damage (128). Other groups have confirmed that lowering homocysteine by folic acid therapy alone (5mg) has a benefit on vascular compliance (131).
As we mentioned previously, renal-transplant recipients (RTRs) are noted for elevated homocysteine and increased risk for CAD. A group of 56 RTRs with elevated homocysteine were randomly assigned to either placebo or vitamin supplementation (folic acid 5mg/day, B6 50 mg/day, B12 400 µg/day) and followed for 6 months (129). In the vitamin group homocysteine levels fell from an average of 21.8 (range 15.5-76.6) to 9.3 (5.8-13.0) while the placebo group saw no change (pre 20.5, post 20.7). Additionally, these patients were measured for carotid intima-media thickness (cIMT), considered to be a marker for atherosclerotic changes and an independent risk factor for myocardial infarction and stroke. In 6 months, RTRs receiving vitamin therapy had an average 32% reduction in cIMT while those on placebo had an increase of 23%. Another study reported that 5 mg of folic acid with 250mg of B6 for 2 years in healthy siblings of patients with premature atherothrombotic disease, decreased occurrence of abnormal exercise electrocardiography tests, which is consistent with a decreased risk of atherosclerotic coronary events (130). These data suggests that outcomes, apart from merely lowering homocysteine, are measurable in these patients.
Another way this can be assessed is to measure outcomes after interventions such as angioplasty. Such was the case in the Swiss Heart Study (132). 556 post-angioplasty patients were randomized to receive either placebo or a vitamin combination (1mg folic, 400 µg B12 and 10mg B6) and followed for 1 year. After adjusting for potential confounders, at the end of one year the group taking the vitamin combination had a 34% reduction in risk compared to the placebo group (combined risks for death, non-fatal myocardial infarction and need for repeat revascularization). Event-free survival and decreased rate of restenosis (re-narrowing after angioplasty) was previously shown with the same moderate doses of vitamins (133). Additional studies by these authors have lead them to conclude that plasma homocysteine is an independent predictor of mortality, nonfatal MI, target lesion revascularization, and overall adverse late outcome after successful coronary angioplasty (134). These data suggest that measuring and treating elevated homocysteine levels in patients with previous CAD is likely to have positive outcomes.
N-Acetyl Cysteine (NAC)
While there is much yet to be done to determine how significant the overall benefit will be in measuring and treating homocysteine levels in the clinical setting, enough evidence is available to suggest ignoring homocysteine levels in patients at risk for cardiovascular disease would be unwise. Knowing base levels of homocysteine in all adult patients may simply be an easy way to measure folate, B6 and B12 status, especially important in those with the C667T polymorphism in the MTHFR gene.
We have presented data showing homocysteine as an independent risk factor for numerous and various diseases, and included plausible mechanisms by which homocysteine may play causative roles in many of them. As treatment of hyperhomocysteinemia with folic acid, vitamin B12 and vitamin B6 is extremely successful in a majority of these patients, there is little reason not to consider this a target for lowering cardiovascular risk. If, by chance, homocysteine is merely an innocuous marker and coincidental with other modifiable risk factors- evidence suggests that the multi-vitamin approach which lowers homocysteine significantly reduces other measures of cardiovascular risk outcomes. While this is unlikely to be independent of homocysteine lowering, the benefit will be realized nonetheless.
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