Homocysteine and Neurologic Disease. | Neurology | JAMA Neurology | JAMA Network
J Clin Hypertens (Greenwich). Sep;6(9); quiz Relationship of homocysteine with cardiovascular disease and blood pressure. Dinavahi. The theory behind this relationship is that homocysteine causes damage to the lining of blood vessels, which increases their likelihood for clot. Epidemiologic evidence suggests that mild hyperhomocysteinemia is associated with increased risk of arteriosclerotic disease and stroke. The relationship.
In patients with end-stage renal disease, Bostom et al. Vitamin Bdependent MS is found in most cells and tissues Inborn errors that affect B12 absorption, systemic transport, intracellular transport, and conversion to the coenzyme form methyl-B12 will produce loss of MS activity and hyperhomocysteinemia 56 Mutations in the structural gene for MS itself are only now being described 80 81 Human MS cDNA contains an open reading frame of nucleotides encoding a polypeptide of amino acids predicted molecular mass, kDa.
Role of homocysteine in the development of cardiovascular disease
On the basis of complementation studies using patient fibroblast cell lines, two types of MS-associated genetic diseases, cblE and cblG, have been described The cblE class may involve a reducing component of the MS system 84whereas cblG is thought to be caused by defective MS apoenzyme 85 Several MS mutations have now been identified in cblG patients 81 87 ; however, the prevalence of these mutations in the general population and their contribution to hyperhomocysteinemia in heterozygous individuals remain to be determined.
Entry of homocysteine into the transsulfuration pathway is catalyzed by B6-dependent CBS, which has limited tissue distribution Several hundred cases of CBS deficiency, the most common form of homocystinuria, have been described When bacterial 89 90 and yeast 91 92 expression systems have been used, close to 40 mutations have been identified in the CBS gene.
Obligate heterozygotes for CBS deficiency might be at greater risk for CVD because of possible increases in basal and postmethionine load total homocysteine 35 51 However, the reliability of assessing heterozygosity based on CBS enzyme activity measurements and postmethionine-loading studies has been questioned A number of genotyping studies have been done; however, they have failed to identify CBS polymorphisms that correlate with CVD 68 95 Clearly, additional studies are needed to assess the role of CBS polymorphism in atherosclerotic disease.
Fruits and vegetables generally contain 0. Peaches and grapes 3. Nuts and cereal grains contain 1. Sources of animal protein have a higher methionine content: By comparison, human milk has only 1.
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Dietary insufficiency or malabsorption of folate, vitamin B12, or vitamin B6 will lead to hyperhomocysteinemia and an increased risk of CVD 97 98 99 Even in well-nourished generally healthy populations, serum folate and B12 inversely correlate with total homocysteine 29 The B vitamins drive homocysteine metabolism, with 5-methyltetrahydrofolate serving as substrate for Bdependent MS in the remethylation of homocysteine back to methionine and vitamin B6 as pyridoxalphosphate as a cofactor for CBS in the transsulfuration pathway Fig.
The large Hordaland study in Norway found that increased total plasma homocysteine was associated with smoking, high blood pressure, increased cholesterol, and sedentary life-style Alcoholics have higher total homocysteine concentrations, perhaps because of malnourishment and malabsorption Heavy coffee consumption is associated with higher homocysteine concentrations as well Certain disease states produce higher total homocysteine concentrations.
Patients with end-stage renal disease have intermediate hyperhomocysteinemia and an increased risk for vascular disease 16 Heart transplant recipients have mild to intermediate hyperhomocysteinemiawhich may in part be related to renal insufficiency Hypothyroidism produces increased total plasma homocysteinebut treatment with l-thyroxine will normalize homocysteine concentrations Mechanisms of Blood Vessel Injury It is usually assumed that reduced homocysteine is the atherogenic form of homocysteine in circulation.
However, in addition to basal concentrations, we should also consider the transient hyperhomocysteinemia that occurs after eating. Within 2 h after methionine loading, reduced homocysteine reaches a maximum and then declines as oxidized forms homocystine and mixed disulfides become increased and reach peak values in 6 h The transient hyperhomocysteinemia seen after methionine loading also occurs after meals, and its magnitude is proportional to protein consumption It can be hypothesized that reduced homocysteine directly alters vascular cell function.
Because reduced homocysteine undergoes oxidation in vivo, one could argue that the homocysteine oxidation products such as hydrogen peroxide, superoxide anion radical, and other reactive oxygen species are the injurious agents. Thus, a second hypothesis is that homocysteine is acting indirectly through its oxidation and formation of reactive oxygen species.
There is little or no evidence in the literature that cysteine is atherogenic. Nevertheless, it is widely believed that homocysteine can alter the surface properties of endothelial cells by changing their phenotype from anticoagulant to procoagulant This is one of the few reports in which physiologically relevant concentrations of homocysteine have been used and in which thiol specificity has been demonstrated.
Upchurch and co-workers reported that homocysteine modulated the expression of glutathione peroxidase and nitric oxide synthase in bovine aortic endothelial cells; however, relatively high concentrations of homocysteine were used. Tsai and co-workers reported that homocysteine was mitogenic to smooth muscle cells by a mechanism involving synergistic induction of cyclin A mRNA expression with serum. However, other thiols, such as cysteine and glutathione, could replace homocysteine, suggesting a general thiol effect on the stimulation of smooth muscle cell proliferation.
Matrix proteins accumulate in atherosclerotic plaques, and recently Majors et al. There have been some interesting in vivo studies in both humans and animal models that support the hypothesis of impaired endothelial cell function in the presence of hyperhomocysteinemia. Van den Berg et al. Deficiency of dietary vitamin B6 causes elevation of blood homocysteine after a meal containing protein, and deficiency of dietary folate or vitamin B12 causes elevation of fasting homocysteine levels.
Dietary protein is also a factor in controlling blood homocysteine levels. Deficiency of dietary protein leads to elevation of blood homocysteine, and increased dietary protein leads to lower homocysteine levels.
These effects are mediated by adenosyl methionine, a metabolic regulator of methionine metabolism that is synthesized from dietary methionine in the liver. Dietary choline, a constituent of wheat germ, vegetables, meats, liver, eggs and seafood, is converted to betaine for conversion of homocysteine to methionine in liver by the enzyme betaine homocysteine transmethylase. The daily requirement of dietary choline is about mg per day.
Betaine, a constituent of wheat germ, spinach, beets, liver, and seafood, lowers plasma homocysteine in doses of 1g or more per day. Homocysteine and Atherogenesis Experiments with rabbits, baboons, and pigs show that injection or feeding of homocysteine causes arteriosclerotic plaques in aorta and peripheral arteries.
High doses cause prominent plaques that closely resemble the fibrous plaques found in human arteriosclerosis and in homocystinuria. Some of the animals develop venous thrombosis and pulmonary embolism, abnormalities that are found in patients with homocystinuria. Feeding fats and cholesterol to animals injected with homocysteine results in fibrolipid plaques with prominent lipid deposition. The molecular basis for production of arteriosclerotic plaques is related to the effect of homocysteine on cellular degeneration, damage to arterial intima, cellular growth, connective tissue formation, deposition of lipoproteins in plaques, and enhanced blood coagulation.
In each of these critical processes in atherogenesis, homocysteine plays a key role. Experiments with cell cultures taken from the skin of a child with homocystinuria show that an abnormal aggregated extracellular matrix results from binding of excess sulfate to the macromolecules.
In these cell cultures, biochemical experiments demonstrated a new pathway for conversion of homocysteine to sulfate, mediated by thioretinamide, an amide formed from homocysteine thiolactone and retinoic acid vitamin A acid.
Deposition of sulfated extracellular matrix is a characteristic feature of early developing arteriosclerotic plaques. Another feature of early plaques is fragmentation and degeneration of elastic fibers. Homocysteine activates the enzyme elastase within arteries, causing fragmentation of the internal elastic membrane.
Homocysteine also causes cultured smooth muscle cells to produce excess collagen, explaining the fibrosis that is characteristic of human and experimental plaques.
Also, arterial smooth muscle cells proliferate in plaques because homocysteine activates cyclins, signaling proteins that mediate cell division. Homocysteine is involved in skeletal growth by releasing insulin-like growth factor and increasing the sulfation of epiphyseal cartilage of animals, explaining the accelerated skeletal growth in children with homocystinuria and the growth of smooth muscle cells in developing arteriosclerotic plaques.
The initial phase in formation of arteriosclerotic plaques involves damage to endothelial and intimal cells, causing cell death and inflammatory reaction within the artery wall. Homocysteine thiolactone causes inflammation, cell death, intravascular coagulation, and stromal and epithelial proliferation with dysplasia when applied to the skin of mice.
These inflammatory, proliferative and prothrombotic effects may be related to increased oxidant stress within cells affected by homocysteine. Lipoproteins, including low-density lipoprotein LDL and high-density lipoprotein HDLcontain homocysteine that is bound to apoB protein by peptide bonds.
The ratio of homocysteine within LDL to homocysteine within HDL is higher in patients with hypercholesterolemia than in normal controls. Reaction of homocysteine thiolactone with normal human LDL in vitro causes increased density, increased electrophoretic mobility, aggregation, and precipitation of LDL particles.
These homocysteinylated LDL particles are taken up by cultured human macrophages to form foam cells, a key process in atherogenesis. Deposition of cholesterol and lipids within fibrolipid arteriosclerotic plaques probably occurs by a similar process in vivo. Epidemiological and Observational Evidence The first human study of homocysteine in vascular disease in showed that oral methionine causes increased levels of homocystine and homocysteine cysteine disulfide in the plasma of patients with coronary heart disease CHD.
Relationship of homocysteine with cardiovascular disease and blood pressure.
Many subsequent studies showed that persons with coronary, cerebral, or peripheral arteriosclerosis have elevated levels of homocysteine in their blood. In patients with early onset of arteriosclerosis, elevation of homocysteine is a more potent risk factor than cholesterol elevation and is similar in strength to the effect of smoking.
The European Concerted Action Study showed that elevation of blood homocysteine potentiates the effect of hypertension, smoking, and cholesterol elevation on cardiovascular risk.