Folate deficiency risk factors

Biod mistry of Fc ie 1-Caib(m Metabolkm Ihirine and Pyrimidine ffiosyndiesis Mitodumdrial Folate tabolism Risk Factors for Folate Deficiency Sig]t of Folate Defidoicy Assesanait of Folate Status Folic dd and Neural Tube Defects... 

Supplements of 400 Ig/d of folate begun before conception result in a significant reduction in the incidence of neural mbe defects as found in spina bifida. Elevated blood homocysteine is an associated risk factor for atherosclerosis, thrombosis, and hypertension. The condition is due to impaired abihty to form methyl-tetrahydrofolate by methylene-tetrahydrofolate reductase, causing functional folate deficiency and resulting in failure to remethylate homocysteine to methionine. People with the causative abnormal variant of methylene-tetrahydrofolate reductase do not develop hyperhomocysteinemia if they have a relatively high intake of folate, but it is not yet known whether this affects the incidence of cardiovascular disease. 

Albumin (human) Epoetin alfa contains albumin, a derivative of human blood. Based on effective donor screening and product manufacturing processes, it carries an extremely remote risk for transmission of viral diseases. No cases of transmission of viral diseases or Creutzfeldt-Jakob disease have ever been identified for albumin. Anemia Not intended for CRF patients who require correction of severe anemia epoetin alfa may obviate the need for maintenance transfusions but is not a substitute for emergency transfusion. Not indicated for treatment of anemia in HIV-infected patients or cancer patients due to other factors such as iron or folate deficiencies, hemolysis, or Gl bleeding, which should be managed appropriately. Hypertension Up to 80% of patients with CRF have a history of hypertension. Do not treat patients with uncontrolled hypertension monitor blood pressure adequately before initiation of therapy. Hypertensive encephalopathy and seizures have occurred in patients with CRF treated with epoetin. 

Vitamins and minerals, whose main dietary sources are other than fruits and vegetables, are also likely to play a significant role in the prevention and repair of DNA damage, and thus are important to the maintenance of long-term health. Vitamin B12 is found in animal products, and deficiencies of B12 cause a functional folate deficiency, accumulation of the amino acid homocysteine (a risk factor for heart disease),46 and chromosome breaks. B12 supplementation above the RDA was necessary to minimize chromosome breakage.47 Strict vegetarians are at increased risk for developing vitamin B12 deficiency. 

Homocysteine, an amino acid associated with eoronary heart disease as a risk factor is elevated in folate deficiency (discussed earlier and also see Chapter 17). If the elevation of plasma homoeysteine is due to folate deficency, supplementation of folate corrects the plasma homocysteine level and may deerease the morbidity and mortality from atherosclerotie disease which can lead to heart attack and stroke. Vitamin Be and Vitamin B12 defieencies can also cause elevated plasma homocysteine 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. ... 

One often-overlooked major factor that may contribute to anemia in the older population is nutritional status. Cross-sectional studies demonstrate a higher prevalence of anemia in low socioeconomic populations, as well as a high prevalence of other nutritional deficiencies. Thus nutritional deficiencies not usually severe enough to affect the hematopoietic system in the younger population may account for anemia in the aged. Edentulous or infirm elderly who may be too ill to prepare their meals are at risk for nutritional folate deficiency. However, unlike cobalamin levels, it has been demonstrated that folate levels increase rather than decline with age. This may be due to the dramatic increase in folate supplements used by the elderly, especially in white women, as well as the fortification of the American diet with folic acid. ... 

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). 

Folate deficiency has been implicated in neural tube defects, including spina bifida, encephalo-celes, and anencephaly. This is true even in the absence of folate-deficient anemia or alcoholism. An inadequate intake of folate also can result in elevations in plasma homocysteine. Since even moderate hyperhomocysteinemia is considered an independent risk factor for coronary artery and peripheral vascular disease and for venous thrombosis, the role of folate as a methyl donor in the homocysteine-to-methionine conversion is getting increased attention. Patients who are heterozygous for one or another enzymatic defect and have high normal to moderate elevations of plasma homocysteine may improve with foUc acid therapy. 

Folate deficiency leads to an elevation of blood homocysteine, a risk factor for cardiovascular disease. 

Hyperhomocysteinemia has long been identified as a risk factor for dementia including Alzheimer s disease (AD) and vascular dementia (VaD) (Morris 2003). The relationship of homocysteine metabolism (methylation and transsulfuration pathways) to deficiencies of the vitamin B complex suggests that hypervitaminosis (Bg, B12 and folate) could contribute to hyperhomocysteinemia (Gonzalez-Gross et al. 2001). 

Deficiencies of vitamin Bg, vitamin B12 and folate may play a role in the pathogenesis of cognitive impairment in the elderly. There are two biological mechanisms by which low levels of vitamin B12 or folate might result in dementia. First, vitamin B12 and folate are essential factors of methylation cycles involved in the synthesis of methionine from homocysteine. With decline in vitamin B status, homocysteine levels increase this is associated with increased prevalence of poor cognitive decline and increased risk of development of dementia and AD. The sequential inability to methylate homocysteine leads to SAH accumulation which is a strong inhibitor of all methylation reactions, competing with SAM for the active site on the methyl transferase... 

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). 

Although folate is widely distributed in foods, dietary deficiency is not uncommon, and a number of commonly used drugs can cause folate depletion. Marginal folate status is a factor in the development of neural tube defects and supplements of 400 fj,g per day periconceptually reduce the incidence of neural tube defects significantly. High intakes of folate lower the plasma concentration of homocysteine in people genetically at risk of hyperhomo-cysteinemia and may reduce the risk of cardiovascular disease, although as yet there is no evidence from intervention studies. There is also evidence that low folate status is associated with increased risk of colorectal and other cancers and that folate may be protective. Mandatory enrichment of cereal products with folic acid has been introduced in the United States and other countries, and considered in others. 

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