Folates plasma levels

In the early stages of vitamin B12 deficiency, classic signs and symptoms of megaloblastic anemia may not be evident and serum levels of vitamin B12 may be within normal limits. Therefore measurement of MMA and homocysteine is useful, as these parameters are often the first to change. Increased levels of serum MMA and homocysteine may be evident, as both of these are involved in enzymatic reactions dependent on vitamin Bn, and a deficiency in vitamin Bn allows for accumulation of these precursors. Elevations in MMA are more specific for vitamin Bn deficiency, while elevated homocysteine can be indicative of either vitamin Bn or folic acid deficiency, but offers greater specificity for folate plasma levels. Low levels of vitamin Bn result in hyperhomocysteinemia, which the majority of data suggest is an independent risk factor for cerebrovascular, peripheral vascular, coronary, and venous thromboembolic disease. Hyperhomocysteinemia may also be linked to dementia and Alzheimer s disease. ... 

Folic acid appears in the plasma approximately 15 to 30 minutes after an oral dose peak levels are generally reached within 1 hour. After IV administration, the drug is rapidly cleared from the plasma. Folic acid is metabolized in the liver. Normal serum levels of total folate have been reported to be 5 to 15 ng/mL normal CSF levels are approximately 16 to 21 ng/mL. In general, folate serum levels less than 5 ng/mL indicate folate deficiency, and levels less than 2 ng/mL usually result in megaloblastic anemia. A majority of the metabolic products appeared in the urine after 6 hours excretion was generally complete within 24 hours. 

Laverdiere C, Chiasson S, Costea 1 et al. Polymorphism G80A in the reduced folate carrier gene and its relationship to methotrexate plasma levels and outcome of childhood acute lymphoblastic leukemia. B/oorf 2002 100 3832-3834. 

Measurement of blood tHcy is usually performed for one of three reasons (1) to screen for inborn errors of methionine metabolism (2) as an adjunctive test for cobalamin deficiency (3) to aid in the prediction of cardiovascular risk. Hyperhomocysteinemia, defined as an elevated level of tHcy in blood, can be caused by dietary factors such as a deficiency of B vitamins, genetic abnormalities of enzymes involved in homocysteine metabolism, or kidney disease. All of the major metabolic pathways involved in homocysteine metabolism (the methionine cycle, the transsulfuration pathway, and the folate cycle) are active in the kidney. It is not known, however, whether elevation of plasma tHcy in patients with kidney disease is caused by decreased elimination of homocysteine in the kidneys or by an effect of kidney disease on homocysteine metabolism in other tissues. Additional factors that also influence plasma levels of tHcy include diabetes, age, sex, lifestyle, and thyroid disease (Table 21-1). 

A CBC, including a peripheral smear and reticulocyte count, should be performed in any elderly patient with symptoms that may be attributed to anemia, along with a physical exam to look for signs of renal or hepatic failure as well as to evaluate for gastrointestinal or genitourinary blood loss. If the reticulocyte count is adequate, blood loss or RBC destruction should be suspected, whereas a low level will indicate decreased RBC production. With a low reticulocyte count, RBC indices should be evaluated and if the MCV is > 100 fL, further evaluation should be performed to discern vitamin B12 deficiency and folate deficiency as possible causes. A vitamin B12 deficiency may be present even when plasma levels of vitamin B12 are within normal range, but elevated levels of MMA will detect the deficiency. A refractory macrocytic anemia in the elderly should raise suspicion of a myelodysplastic or leukemic syndrome. 

An increased plasma level of homocysteine is regarded as a risk factor for cardiovascular disease and the development of arteriosclerosis. Homocysteine concentrations in plasma are reduced by remethylation and transsulfuration (Komarnisky et al. 2003). The remethylation is catalyzed by methionine synthase, which in turn is influenced by vitamin B12 and folate. The transsulfura-tions depend on cystathionine 3-synthase. A dietary deficiency of vitamins B, B12 and folate, accompanied by a high protein intake, can cause hyperhomocystinemia in humans (Jacobsen 1998). Furthermore, a genetic disorder of enzymes involved in the metabolism of homocysteine leads to hypercystinuria (Mudd et al. 1989). 

Dimopoulos, N., Piperi, C., Salonicioti, A., Psarra, V., Gazi, F., Papadimitriou, A., Lea, R.W., and Kalofoutis, A. 2007. Correlation of folate, vitamin B12 and homocysteine plasma levels with depression in an elderly Greek population. Clin Biochem 40 604-608. 

Elevated serum MMA and tHcy concentrations can be considered alternative specific metabolic parameters of cobalamin deficiency. Measurement of functional metabolite MMA requires sophisticated equipment and is, therefore, unsuitable for routine use. Total homocysteine is a more sensitive analyte than tfii2 in diagnosing subclinical vitamin B12 deficiency because its plasma levels increase before clinical symptoms appear. However, the lack of specificity of this analyte represents a serious limit to its use. Total homocysteinemia depends on genetic or physiological factors, life style, diseases in progress, and drugs. HHCY is caused by folate or vitamin Bg deficiency and renal failure. 

Homocysteine arises from dietary methionine. High levels of homocysteiae (hyperhomocysteinemia) are a risk factor for occlusive vascular diseases including atherosclerosis and thrombosis (81—84). In a controlled study, semm folate concentrations of <9.2 nmol/L were linked with elevated levels of plasma homocysteiae. Elevated homocysteine levels have beea associated also with ischemic stroke (9). The mechanism by which high levels of homocysteine produce vascular damage are, as of yet, aot completely uaderstood. lateractioa of homocysteiae with platelets or eadothehal cells has beea proposed as a possible mechanism. Clinically, homocysteine levels can be lowered by administration of vitamin B, vitamin B 2> foHc acid. 

With investigations of phytochemicals and functional foods, the outcome measure is generally going to be a biomarker of disease, such as serum cholesterol level as a marker of heart disease risk, or indicators of bone turnover as markers of osteoporosis risk. Alternatively, markers of exposure may also indicate the benefit from a functional food by demonstrating bioavailability, such as increased serum levels of vitamins or carotenoids. Some components will be measurable in both ways. For instance, effects of a folic acid-fortified food could be measured via decrease in plasma homocysteine levels, or increase in red blood cell folate. 

Figure 22.6 How various factors increase the risk of atherosclerosis, thrombosis and myocardial infarction. The diagram provides suggestions as to how various factors increase the risk of development of the trio of cardiovascular problems. The factors include an excessive intake of total fat, which increases activity of clotting factors, especially factor VIII an excessive intake of saturated or trans fatty acids that change the structure of the plasma membrane of cells, such as endothelial cells, which increases the risk of platelet aggregation or susceptibility of the membrane to injury excessive intake of salt - which increases blood pressure, as does smoking and low physical activity a high intake of fat or cholesterol or a low intake of antioxidants, vitamin 6 2 and folic acid, which can lead either to direct chemical damage (e.g. oxidation) to the structure of LDL or an increase in the serum level of LDL, which also increases the risk of chemical damage to LDL. A low intake of folate and vitamin B12 also decreases metabolism of homocysteine, so that the plasma concentration increases, which can damage the endothelial membrane due to formation of thiolactone.

Therapy, in the short term, is with intravenous unfractionated or subcutaneous low molecular weight heparin. Aspirin, given in low doses between 50 and 100 mg per day, is sufficient to diminish platelet-vessel interaction. Alternatives include 100-200 mg of sulphinpyrazone once or twice a day or dipyridamole where 100 mg four times a day can be used on its own or between 25 and 75 mg combined with aspirin three times a day. More recently thiopy-ridines, as a class, has been shown to have equivalence at 250 mg twice a day. In hyperhomocysteinaemia the risk is reduced by 5 mg of folate and 100 mg of vitamin Bg daily, with addition of oral vitamin Bi2 of less clearly defined benefit. The effect of this intervention requires re-assay at 3-monthly intervals, following standard methionine challenge, to ensure that suitable suppression has been achieved in the plasma amino acid level (Table 5). 

The homocystinurias are a group of disorders involving defects in the metabolism of homocysteine. The diseases are inherited as autosomal recessive illnesses, characterized by high plasma and urinary levels of homocysteine and methionine and low levels of cysteine. The most common cause of homocystinuria is a defect in the enzyme cystathionine /3-synthase, which converts homocysteine to cystathionine (Figure 20.21). Individuals who are homozygous for cystathionine [3-synthase deficiency exhibit ectopia lentis (displace ment of the lens of the eye), skeletal abnormalities, premature arte rial disease, osteoporosis, and mental retardation. Patients can be responsive or non-responsive to oral administration of pyridoxine (vitamin B6)—a cofactor of cystathionine [3-synthase. Bg-responsive patients usually have a milder and later onset of clinical symptoms compared with B6-non-responsive patients. Treatment includes restriction of methionine intake and supplementation with vitamins Bg, B, and folate. 

Vitamins B6, B12, and folate An elevated plasma homocysteine level is associated with increased cardiovascular risk (see p. 263). Homocysteine, which is thought to be toxic to the vascular endothelium, is converted into harmless amino acids by the action of enzymes that require the B vitamins—folate, B6 (pyridoxine), and B12 (cobalamin). Ingesting foods rich in these vitamins can lower homocysteine levels and possibly decrease the risk of car diovascular disease. Folate and B6 are found in leafy green veg etables, whole grains, some fruits, and fortified breakfast cereals. B12 comes from animal food, for example, meat, fish, and eggs. 

Several studies have demonstrated an association between plasma tHcy levels and extent of CAD in populations not exposed to fortification of flour products with folic acid, even after controlling for conventional risk factors (26,27). In contrast, Brilakis et al. (28) found no association between plasma tHcy and angiographic CAD in a North American population consuming cereal grain flour fortified with folic acid. Silberberg et al. (29) found an association between plasma folate and CAD independent of tHcy. 

Choline has been shown to be essential to the body. In a landmark study in 1991, Zeisel et al. (246) showed that healthy men with normal folate and Vitamin B12 status fed a diet deficient in choline have diminished plasma choline and PC concentrations and subsequently developed liver damage. In other words, when other nutrients are adequate, the body is not able to produce choline in quantities sufficient to prevent liver damage as assessed by elevated serum levels of alanine-ami-notransferase (ALT), a critical liver enzyme. These data served as the supporting... 

The amount of vitamin B12 in the serum sample is determined as follows. The amount of radioactive [ Co]cobalamin bound to the beads is measured. The purpose of using the beads is to facilitate the separation of bound P CoJcobalamin from the nonbound [ Co]cobalamin remaining in solution (floating around versus sinking to the bottom of the test tube). High levels of bound radioactivity indicate that the scrum sample contains low vitamin levels. Low levels of bound radioactivity indicate that the scrum contains high levels of vitamin. Plasma folate is... 

A study of 2K human subjects revealed that treatment with three vitamins together (folate, vitamin and vitamin Bu) can provoke a decline of plasma homt>cysteine from an initial level of about 12 piM to the lower level of 8 xM (Naurath ei a]., 1995). A study of 100 men with moderate levels of plasma homocysteine (18-40 pM) involved separate supplements of placebo, folic acid, vitamin 15i2, or vitamin E. Folic add alone resulted in a 40% decline in plasma homocysteine. Vitamin B] alone provoked a 15% decrease in the amino acid, while vitamin... 

A study of 1401 subjects involved measuring plasma homocysteine and measuring the lesions in the carotid artery, one of the arteries in the body that tends to acquire atherosclerotic lesions. The thickness of the lesions were measured by ultrasonography. Plasma folate, vitamin Bg, and vitamin B12 were also measured. A correlation was found between narrowing of the artery and homocysteine levels at above 15 xM homocysteine. A correlation with narrowing of the artery was also found with folate levels below 2.5 ng/ml, and with vitamin Bg levels below 30 nM (Selhub et al, 1995). A study of 231 normal subjects and 304 patients with atherosclerosis (coronary artery under 30% normal diameter) revealed a striking correlation between plasma homocysteine of 12 pM, or greater, and atherosclerosis (Robinson et al, 1995). These studies help define an upper limit of acceptable plasma homocysteine levels. 

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