Hyperhomocysteinemia and the Endocrine System: Implications for Atherosclerosis and Thrombosis

I. Introduction II. Methionine-Homocysteine Metabolism A. Methionine metabolism B. Regulation of remethylation and transsulfuration of H(e) III. Nomenclature and Methodology in the Measurement of Plasma H(e) A. Methionine load test IV. Determinants of Plasma Homocysteine A. Physiological B. Genetics of hyperhomocysteinemia C. Nutritional D. Hormones and H(e) metabolism V. Homocysteine and Diabetes Mellitus (DM) A. Hyperhomocysteinemia, renal failure, and diabetic nephropathy B. Effect of glucose and insulin on H(e) metabolism VI. Hyperhomocysteinemia and Cholesterol Metabolism VII. Hyperhomocysteinemia in Premature Vascular Disease A. Epidemiological and prospective studies B. Studies in patients with established vascular disease C. Negative studies D. Effect of low plasma H(e) on cardiovascular disease VIII. Possible Mechanisms of Accelerated Vascular Disease in Homocysteinemia A. Platelet dysfunction B. Coagulation abnormalities C. Effects on the endothelium D. Effects of hyperhomocysteinemia on the arterial wall E. Coinheritance of factor V Leiden in homocystinuria IX. Management of Hyperhomocysteinemia A. Prevention of hyperhomocysteinemia B. Treatment of hyperhomocysteinemia X. Conclusion HOMOCYSTEINE (H(e)) is a nonprotein-forming, thiol-containing amino acid formed by demethylation of methionine. It is metabolized by remethylation to methionine or by transsulfuration to cysteine. An elevated plasma H(e) level may occur as a result of inherited disorders, which alter enzyme activity in the transsulfuration and remethylation pathways. Alternatively, nutritional deficiencies of essential cofactors or enzyme substrates, including cobalamin (vitamin B12), folate, or pyridoxine (vitamin B6), can result in blockade of H(e) metabolic pathways. An elevated plasma H(e) level has recently been established as an independent risk factor for thrombosis and vascular disease (1–11). However, the relationship between hyperhomocysteinemia [HH(e)] and cardiovascular disease remains controversial. Although some prospective studies have confirmed that H(e) is an independent risk factor for cardiovascular disease (3, 6), other studies have not found such a relationship (12, 13). Because of the possibility of reducing plasma H(e) with vitamin therapy, this issue has received considerable public attention. However, no large clinical trials have demonstrated a reduction in cardiovascular risk. Ongoing clinical trials are examining the possibility that vitamin therapy to lower H(e) levels may prevent cardiovascular disease. Homocystinuria is an inherited disorder characterized by severely elevated plasma H(e). Homocystinuric children are known to develop premature vascular disease involving all major blood vessels (14, 15). McCully (16) first drew attention to a possible link between elevated plasma H(e) and vascular disease, making the seminal observation that extensive arterial thrombosis and atherosclerosis commonly occurs in children with homocystinuria. Boers et al. (17) highlighted the association between accelerated vascular disease and moderate elevation in plasma H(e), without the other manifestations of homocystinuria. Since then, there has been considerable interest in mild HH(e) as a risk factor for coronary artery disease, stroke, and peripheral vascular disease. The understanding of the different etiologies of HH(e) is changing because of the ability to discriminate between the types of mutations present in inherited disorders, the ability to distinguish between homozygous and heterozygous mutations, and recognition of factors that modify H(e) metabolism. A mutation resulting in a thermolabile variant of the methylene tetrahydrofolate reductase (MTHFR) enzyme is common, occurring in one-third to one-half of alleles and varying slightly with the population studied. In the homozygous state, the thermolabile variant is found in about of the population hyperhomocysteinemia has been in homozygous for this as occurs with low cardiovascular risk is not with the mutation However, the risk of cardiovascular disease is in with low A of patients with cardiovascular disease have methionine load a possible in However, mutations of are occurring in of the population the of load HH(e) that occurs in patients with cardiovascular disease that of HH(e) are to possible such factors are nutritional and highlighted a between nutritional and an of a The of this is to the on H(e) of and of vascular disease in In the of between the and H(e) metabolism. Methionine is to H(e) and The metabolism of H(e) occurs the transsulfuration or the remethylation It is that the remethylation is in the and that transsulfuration is a methionine load such as a H(e) with to this is by and is on of vitamin as a is to by the enzyme and is a Alternatively, methionine may the remethylation a is to H(e). In this tetrahydrofolate is to tetrahydrofolate in a by with as a tetrahydrofolate a to H(e) in a by and Alternatively, the may by in a by and methionine. The is vitamin of the metabolic in metabolism. is by et by the of with of the metabolic in metabolism. is by et by the of with H(e) is metabolized by pathways. and that the of H(e) between methionine and the occurs by by have the that of H(e) metabolic with the of the other metabolic to However, this has been demonstrated in of in is and methionine is by to as a to a of including and for a major of is the of and is to H(e), which a of In levels found to low in patients with coronary artery disease However, may not levels in other such as the which may Studies in have demonstrated that is an of and an of and have that the ability of to as an a by which remethylation and transsulfuration can is resulting in remethylation of H(e) for methionine is occurs a methionine of methionine is by of H(e) the transsulfuration by of the of the metabolic by Regulation of of H(e) metabolism by of H(e) Regulation of of H(e) metabolism by of H(e) levels may the of plasma H(e). is on the and other factors that and on H(e) metabolism. the to a for of in is or can Plasma H(e) is and is for C. The plasma can Plasma for have been in some and the of H(e) in such plasma remains to Homocysteine is the and is the of the and the of this of to as the H(e) and to as is between the and in the H(e) is as or in the and H(e) in the It may to in and of in this In patients in H(e) levels are about of the H(e) is to by a elevated H(e) the of H(e) in the an of the H(e) and can to of the H(e) The H(e) is as the which is by is by with reducing such as or to H(e) with with or without and with with to not have been for H(e) that to including an and an for the of plasma H(e) are not of for between and and for the are between and Studies on a population for have that for a a the the for the commonly The methionine load test is essential in the of HH(e) because for have methionine load test in the of H(e) levels that an an of the is in However, this is by the of et al. activity in with an et al. have the of the in HH(e) in patients with vascular disease. A large of such patients have plasma H(e) with an and the of of HH(e) and HH(e) levels are in a The is an blood are and a methionine An load test in a plasma H(e) level factors have been found to a in the or of HH(e) et al. a large of and with major and that a major of plasma H(e) and that a lower The in H(e) between and in have Plasma H(e) with and an independent risk factor for vascular disease in the The and other vitamin deficiencies known to in the are to factors to HH(e) are between plasma H(e) and and vitamin Plasma H(e) in in the of this of vitamin is in load plasma H(e) H(e) have been found between plasma H(e) and acid and that may to the between H(e) metabolism with of and acid Plasma with plasma H(e) and may an in H(e). The of of H(e) with to cardiovascular disease is In the H(e) elevated plasma H(e) with elevated and of In a et al. demonstrated that blood plasma and of of plasma H(e) in not have a of disease. It is possible that H(e) in plasma is an vascular Plasma H(e) a and In plasma H(e) to lower a The for this is not other disease and in plasma H(e). The recently association between HH(e) and is in factors are in The of mutations, nutritional and are of elevated plasma H(e) levels of elevated plasma H(e) levels In factors alter plasma H(e) levels or by abnormalities in the enzyme mutations with HH(e) have been including mutations and mutations of the mutations for a that is present in one-third to one-half of in a thermolabile variant of the The enzyme has been to no has been found between H(e) levels and of the cobalamin or that the of the are in A of cobalamin enzyme mutations is The of and mutations are in mutations are as with H(e) of mutations the risk of arterial or disease remains an of studies have not the of and have elevated H(e) levels with risk of vascular disease. is to the risk of vascular disease, studies to vitamin vitamin vitamin B12), H(e) and vascular studies may that not to the risk of vascular disease. by vitamin may the risk of vascular disease. of mutations in in H(e) metabolism to enzyme plasma H(e), and risk of vascular disease a studies that have and vitamin that in patients the risk of coronary artery disease and is not have this mutation may the this the mutation is as In patients with low to low H(e) levels are of mutations in in H(e) metabolism to enzyme plasma H(e), and risk of vascular disease a studies that have and vitamin that in patients the risk of coronary artery disease and is not have this mutation may the this the mutation is as In patients with low to low H(e) levels are mutations are the of homocystinuria. of the result in an enzyme with for of or H(e). have been found to have of activity In activity of the enzyme as a of H(e) to abnormalities in the have H(e) and an not a heterozygous in have to a heterozygous to an a is to enzyme activity and the for in studies mutations with H(e) levels and risk of vascular disease The has been to the of is inherited in an resulting in homozygous and heterozygous of the for the has to mutations et al. have characterized of the mutations as a a or a The first mutations for of alleles mutation with the occurring in of an the in of a population et al. have that the for a mutation is to and that of with premature vascular disease are heterozygous for An mutation by et al. a in the of of the which an the has been in with the the is in of the In the a premature et al. that not the premature or that the not in a mutation because the mutation is the the there is no of the The of this mutation with the population studied. et al. a of in a population the mutation has been to occur in of mutation has been by et al. in a vitamin mutation a and in that to in to the other mutations that result in an that the activity of this mutation with the of the the reduction of to The is on different mutations for the have been of mutations result in The of mutations are a which an to a and a which an to a mutation in the a in a thermolabile variant of the mutation a and an for a in the The of this slightly with the population of are homozygous for this The homozygous thermolabile is characterized by an enzyme activity of about of the the The enzyme is thermolabile there is activity to C. HH(e) not occur in heterozygous for this and to occur in are that for this mutation may have a Methionine Methionine to the of a to H(e) the Methionine that in a not with H(e) level and not to a risk factor for vascular disease, clinical have methionine have mutations in that has in a in the methionine mutations of methionine that are with hyperhomocysteinemia have been the risk of the risk of vascular disease and hyperhomocysteinemia in patients with the homozygous thermolabile for In no risk for vascular disease or hyperhomocysteinemia is present in for this et al. cardiovascular patients and and found that of the cardiovascular patients of homozygous for the thermolabile a risk of premature cardiovascular disease for the homozygous and not for levels in In et al. in the that the thermolabile in with hyperhomocysteinemia levels low An risk for on the of the homozygous not In by et al. the of the homozygous not the risk of thrombosis patients et al. that the of the homozygous and a not different between patients with coronary artery disease and patients with the homozygous have H(e) levels the levels the et al. that for the H(e) levels with the levels et al. that with the may have an and et al. that levels are lower in homozygous for the The large prospective by et al. the mutation with cardiovascular disease for studies that may have an and that in the of levels are not risk for hyperhomocysteinemia or vascular disease. Plasma H(e) is a of et al. demonstrated that in with plasma the H(e) is on a lower levels of plasma folate, the plasma H(e) et al. in a large prospective of that the the of all of cardiovascular disease the of However, there have been no trials of the of acid on cardiovascular disease. is about the of acid that is to plasma H(e). et al. that have lower plasma H(e) The for in the is It has been that an of of acid the level prevent an plasma H(e) in of the population et al. that with of acid in plasma H(e) by the of to et al. a in of or acid low to or with of acid with or without other for to no in plasma H(e) in acid of to in and and a in plasma H(e) no in vitamin or cysteine. The H(e) in the plasma H(e) or the H(e) is found to a risk factor in vascular disease, with levels of acid have a on the of the disease in the et al. possible between and in that in in is for and for The between and The in is in with the of to prevent an in plasma H(e) levels is by a of A of trials with acid that of the with acid with vitamin to plasma H(e) by to about to to such population to of HH(e) and cardiovascular disease and It is that the of vitamin is an in the of H(e) to The enzyme in this is Because vitamin is not in pyridoxine result in HH(e) the transsulfuration is such as a methionine the that to heterozygous may result vitamin vitamin for develop HH(e) a methionine load However, clinical studies have demonstrated a of a relationship between plasma H(e) and vitamin In by plasma H(e) levels In patients with with vitamin plasma H(e) a methionine load with by with pyridoxine for pyridoxine in patients have HH(e) a methionine a in patients with premature cardiovascular disease. The of vitamin in the remethylation of H(e) to methionine is and HH(e) is a of vitamin However, the relationship between vitamin levels and cardiovascular disease is In the plasma H(e) a association with plasma a association with plasma vitamin in the of plasma plasma H(e) with in the Homocysteine with of and vitamin not vitamin of the studies of HH(e) in patients with vascular disease have with vitamin in the of patients with HH(e) with vitamin to have on plasma H(e). Studies have been to the of in the of H(e) metabolism and in abnormalities not the of HH(e) in patients with vascular disease. is of methionine which is not with mutations of the et al. that activity in of patients with other A for the activity that of as as other in H(e) metabolism may by is some to that has an on H(e) the is not Plasma H(e) in to that in a possible of other factors such as vitamin a may have an on the activity of some of the in H(e) metabolism studies are to this have the of on plasma H(e). et al. and plasma H(e) in and without a of vascular disease. and plasma H(e) in as with The to large to as an of in plasma H(e) a of is and is to to In plasma H(e) and to et al. that levels of and plasma H(e) in not of of In in the level of plasma H(e) lower that of of in that in with and with a in vitamin folate, and The in H(e) levels may the in cardiovascular disease that occurs in this and by therapy However, cardiovascular risk factors with and is to the lower of vascular disease in and in may to the lower of In a prospective et al. H(e) in The H(e) by with a in a H(e) level with in a low are to the of on cardiovascular including on and However, is possible that a of plasma H(e) to this in to not and H(e) in an with plasma H(e) by a of in with independent of the in with the of that there is an In there may an to a elevation in plasma with et al. the of of on H(e) in Plasma H(e) levels not or with It is that not plasma H(e) levels in However, the of et al. has in that plasma H(e) the may have an of on H(e). Since has a on plasma H(e) an is for the in plasma H(e) between and possible for this is that is to amino acid and to in in all of which may in the plasma H(e) in Plasma H(e) with in and In et al. demonstrated that the in plasma H(e) and for In plasma H(e) in the in between and may an factor in the between and in plasma H(e) of is because of the major in occurring in In this may that with the plasma H(e) by a of on plasma H(e) Plasma H(e) are in with or a of An elevated plasma H(e) in has been In a et al. demonstrated that plasma H(e) in patients with In plasma H(e) in patients not that of HH(e) may the risk of cardiovascular disease in that is to disease is is patients with has an and a in patients without cardiovascular risk such as and are in patients with not this in disease that H(e) may a risk factor for cardiovascular disease in this population et al. that HH(e) a methionine load in of patients with disease, in patients with with nephropathy been that and patients the of studied. In et al. found that plasma H(e) elevated in some patients with and this with vitamin It is possible that by patients with and In a of HH(e) and the risk of cardiovascular disease, patients to and glucose The the of HH(e) and with to cardiovascular disease. HH(e) in of for and the in H(e) for peripheral for coronary for and for cardiovascular disease. by glucose and for the risk factors and the in H(e) for cardiovascular disease in glucose in glucose and in for the of the association between HH(e) and cardiovascular disease is for patients with in in that to and may to an of insulin and on H(e) metabolism and cardiovascular disease. and HH(e) are with In a to the of elevated H(e) levels that by plasma of acid an of in patients with Plasma elevated in with vascular disease. The of hyperhomocysteinemia not with a in plasma and of vascular disease in patients have hyperhomocysteinemia is other studies of patients with have confirmed that plasma H(e) levels are in the of the disease. However, et al. that plasma H(e) in patients nephropathy and an elevated plasma recently demonstrated that diabetic patients with the and metabolic to a in plasma H(e) that this in plasma H(e) by of blood et al. that plasma H(e) and a methionine elevated in patients with and in patients The patients with and HH(e) plasma levels and a of diabetic including disease. a relationship between plasma H(e) and as as a relationship between plasma H(e) and plasma HH(e) an cardiovascular risk factor in patients with to the risk of cardiovascular disease in this of with between plasma H(e) and with et Diabetes Diabetes between plasma H(e) and with et Diabetes Diabetes between plasma H(e) and plasma in patients with with et Diabetes Diabetes between plasma H(e) and plasma in patients with with et Diabetes Diabetes et al. demonstrated an of H(e) and In in there an of H(e), a between and H(e), which to the cardiovascular in patients with However, the of H(e) in the that found in plasma in patients with and Effect of the of H(e) and HH(e) on in The of has been with et Diabetes Diabetes Effect of the of H(e) and HH(e) on in The of has been with et Diabetes Diabetes The of et al. are by the that there a of in the in with H(e). It that as a result of the possibility remains that renal activity may in the of diabetic have confirmed the association between plasma H(e) and in patients with et al. plasma H(e) in diabetic patients and with plasma H(e) patients with and to to plasma H(e) In patients with with plasma H(e) patients without may have been to the that the patients with of with a et al. recently the relationship between and in a between and and load plasma H(e) in patients plasma H(e) that patients with and HH(e) and arterial blood with a plasma H(e). a between plasma and arterial et al. recently a relationship between H(e) and risk of In a of to and glucose H(e) with the of independent of other risk factors including and renal in H(e), the risk of present by about The that hyperhomocysteinemia may the link between and the risk of cardiovascular disease. However, is to that is with other cardiovascular risk all of which to cardiovascular disease. in a et al. demonstrated that plasma H(e) in patients with with or without is to the that HH(e) in cardiovascular disease in patients with and The of renal disease on H(e) metabolism has been is of considerable to and patients with as are risk of renal Studies to the of HH(e) in patients with renal and are of considerable to patients with of the of renal and in plasma H(e) is to the in of some of this elevation may to of H(e), other may have considerable of which may an of the HH(e) in renal disease. vitamin has been to lower plasma H(e) in levels elevated in patients Hyperhomocysteinemia has been demonstrated renal and may by It is that insulin has on and amino acid metabolism. However, on H(e) metabolism has not been studied. a the plasma H(e) to Plasma H(e) levels by in not in patients with that to the of insulin on glucose may with to the of insulin on H(e) levels in patients with a to on H(e) may to the cardiovascular disease with the insulin and It is that insulin plasma the methionine Plasma amino acid including an glucose load and the in plasma insulin However, in patients with this in amino not a possible to on amino in The in plasma methionine may of methionine or metabolism the transsulfuration resulting in levels of H(e). and plasma H(e) levels may a in is to the of insulin on the of the activity of the and transsulfuration A has demonstrated an relationship between plasma H(e) and insulin in with However, because of the abnormalities in metabolism and present in is to a relationship between the is in other to insulin the of by a on H(e) and activity of in this metabolic and in an insulin by a and of and with a the of the the and The plasma H(e) elevated in the and enzyme activity lower in the with In enzyme activity and levels elevated in the with between plasma H(e) and and between plasma insulin and activity and between and The relationship the of and and that on H(e) metabolism may In to which may with to of and and may to the accelerated disease with However, to that the in and the may not to The of of on H(e) metabolism has not been studied. that insulin and not alter plasma H(e) et al. that not plasma H(e). However, in a clinical of to in patients with coronary artery disease, there a moderate and in plasma H(e) with with a in levels In HH(e) is not in patients with and may a in the accelerated cardiovascular disease in The for this of HH(e) is not a for insulin in of plasma H(e) levels and that insulin may to and of the possible between and Homocysteine and Homocysteine and Possible to premature atherosclerosis in Possible to premature atherosclerosis in is that the risk for vascular disease HH(e) is independent of abnormalities in metabolism. However, the risk factors in the and may have an In patients risk for vascular disease by of plasma H(e) In the risk of for the of plasma H(e) that for the possible to H(e) in this population with a possible for risk factor Plasma H(e) has been to with a of cardiovascular disease in children with An elevated is as a factor However, a is not in the of an elevated plasma H(e) in to that H(e) may with an elevated by of However, this remains controversial. It has been that H(e) activity in and to a reduction in levels for the in is a of the enzyme that the reduction of However, in are not by clinical in to in in with in the of with vascular disease, plasma are not elevated levels by are by other In patients with homocystinuria a of as a of et al. the of and the to of in patients with homocystinuria. The of and of not between patients and studies are on to in patients with It is that children have homozygous homocystinuria develop premature and vascular disease. patients are to in or in the that elevated H(e) levels are a risk factor for arterial disease. In the first prospective of H(e) levels as a cardiovascular risk with no vascular disease plasma and for Plasma H(e) levels in a in The risk for in in the for H(e) levels in the for other known risk factors for vascular disease In et al. the a prospective of between the of and Homocysteine levels in of disease, and Homocysteine levels in the that of disease in the with H(e) levels in the the risk for other for in the In a the et al. the association between H(e) and of to there of with no of H(e) in and for and without a of not develop a or H(e) in a in the risk of in the and of the H(e) to the for and not the association to the that H(e) is a and independent risk factor for studies have to the of HH(e) in patients with premature and accelerated vascular disease. in this by the first by Boers et al. (17) found elevated plasma H(e) a methionine load in of patients with peripheral vascular and disease for other risk plasma H(e) has been found to in patients with peripheral vascular disease with in H(e) a methionine load occur in of patients with vascular disease in It that the the population levels In a of studies of H(e) in vascular disease, et al. that of H(e) an independent risk factor for In of the coronary artery disease risk to H(e). The for of coronary artery disease plasma H(e) a level of is for and for et al. patients the of with thrombosis and arterial disease and found moderate HH(e) in and of The of HH(e) as a methionine load studies have confirmed the of HH(e) in and thrombosis the in In this of vascular disease with of of The risk for vascular disease in the of plasma H(e) with the lower Methionine an of risk A between plasma H(e) and risk. The risk to and independent of other risk factors including and An elevated plasma H(e) a on risk in and with to have a lower risk of vascular disease with of vitamin to lower plasma H(e) A has established the of plasma H(e) levels in patients with established coronary artery disease in patients with confirmed coronary artery disease of and A relationship between plasma H(e) levels and found a of patients with a plasma H(e) as with of with a plasma H(e) The of H(e) levels to remains for other It is to that plasma H(e) levels are a in the population and there is no which the risk for In an elevated and plasma H(e) a association with risk of coronary atherosclerosis association a of plasma H(e), without a which there no risk. Hyperhomocysteinemia to have association with artery disease highlighted in a of in the A in the of