Deficiency of folate or vitamin

Most hematological adverse effects associated with trimethoprim have been reported with co-trimoxazole. These include macrocytic and megaloblastic anemia, aplastic anemia, neutropenia, hypersegmentation of leukocytes, thrombocytopenia, and pancytopenia (12,61-63,75-79). Sulfonamides alone have not been associated with folate deficiency, but in combination with trimethoprim they can deplete folate stores in patients with preexisting deficiency of folate or vitamin B12 (80). Treatment with co-trimoxazole can impair the function of mobilized autologous peripheral blood stem cells (81). 

Hemolysis, if sufficiently severe, produces an LD isoenzyme pattern similar to that in myocardial infarction. Megaloblastic anemias, usually resulting from the deficiency of folate or vitamin cause the erythrocyte precursor cell to break down in the bone marrow (ineffective erythropoiesis), resulting in the release of large quantities of LD-1 and LD-2 isoenzymes. Marked elevations of the total LD activity in serum— up to 50 times the upper reference limit—have been observed in the megaloblastic anemias. These elevations rapidly return to normal after appropriate treatment. 

Deficiency of folate or vitamin Bn can cause hematological changes similar to hereditary orotic aciduria. Folate is directly involved in thymidylic acid synthesis and indirectly involved in vitamin Bn synthesis. Orotic aciduria without the characteristic hematological abnormalities occurs in disorders of the urea cycle that lead to accumulation of carbamoyl phosphate in mitochondria (e.g., ornithine transcarbamoylase deficiency see Chapter 17). The carbamoyl phosphate exits from the mitochondria and augments cytosolic pyrimidine biosynthesis. Treatment with allopurinol or 6-azauridine also produces orotic aciduria as a result of inhibition of orotidine-5 phosphate decarboxylase by their metabolic products. 

Deficiencies of folate or vitamin B12 can canse megaloblastic anemia, in which the cells are larger than normal. Folate and B12 are reqnired for DNA synthesis (see Chapters 40 and 41). When these vitamins are deficient, DNA replication and nnclear division do not keep pace with the matnration of the cytoplasm. Conseqnendy, the nuclens is extraded before the requisite number of cell divisions has taken place, and the cell volume is greater than it should be, and fewer blood cells are produced. 

The availability of Mg +, K+, and the folate coenzymes may also be considered. The two cations are probably not rate-limiting, although K+ concentrations do fluctuate in cells. Little is known about the concentrations of total folic acid or of individual folate coenzymes, relative to tissue requirements for them. That this cofactor may be in excess was suggested by a recent study (39) in which a 95% decrease in total H4-folate was induced without causing any change in growth rate of the cells concerned. Others have found, however, that dietary deficiency of folate or vitamin Bi2 leads to increased urinary excretion of aminoimidazole carboxamide (40, 4D-... 

Anemia is defined by abnormally low circulating hemoglobin concentrations. A variety of etiologies exist for anemia, including dietary deficiencies of folate or vitamin B12 (pernicious or macrocytic anemia), infections and inflammatory states (anemia of chronic disease), and conditions that result in insufficient production of red blood cells (aplastic anemia) or excessive destruction of red blood cells (hemolytic anemia). However, worldwide, the most prevalent form of anemia is that of iron deficiency, which causes anemia characterized by hypochromic and normo- or microcytic red blood cells. Iron deficiency anemia remains a health problem in both the developed and the developing world. This article discusses the metabolism of iron the assessment of iron deficiency iron requirements across the life span and the consequences, prevention, and treatment of iron deficiency and iron deficiency anemia. 

Pathophysiologically, this arises in three ways. First, output may be ineffective as occurs with deficiencies of folate and vitamin B12, or in the myelodys-plastic syndromes. Second, extensive infiltration by malignant disease or fibrous is to blame. Third, the blood-forming tissue is deleted - usually reversible... 

Isolated nutritional deficiencies. Iron, folate, or vitamin Bi2 deficiency may manifest as anemia, which may be mild vitamin K deficiency as a bleeding tendency and vitamin D deficiency as bone disease. They are reflected by a variety of signs and symptoms (glossitis, pallor, dermatitis, petechiae, bruising, hematuria, muscle or bone pain, or neurological abnormalities). 

Since the end products of pyrimidine catabolism are highly water-soluble, pyrimidine overproduction results in few clinical signs or symptoms. In hypemricemia associated with severe overproduction of PRPP, there is overproduction of pyrimidine nucleotides and increased excretion of p-alanine. Since A, A -methyl-ene-tetrahydrofolate is required for thymidylate synthesis, disorders of folate and vitamin Bjj metabofism result in deficiencies of TMP. 

Prescribing perspective necessitates an awareness of this diagnostic possibility and its reliable separation from simple folate or vitamin B12 deficiency. Here cytogenetic studies may be crucial. Once the diagnosis has been made a number of individuals are seen not to be suitable for aggressive intervention. In this situation the use of stimulatory peptides is of value but are expensive and should therefore be used only on the recommendation of an experienced clinical haematologist. 

If lack of response or failure to maintain response occurs, checkfor causative factors (e.g., folate or vitamin deficiency, occult blood loss, malignancy)... 

Elevated Hey levels can also occur in nutritional deficiencies of vitamin B12 (cobalamin) and folate. Folate or vitamin B12 deficiency can even lead to tHcy levels as high as those seen in the genetic homocystinurias [13]. In addition, a reciprocal relationship between blood levels or intake of these vitamins and tHcy concentrations... 

Deficiencies of vitamin B12 can result from either low dietary levels or, more commonly, from poor absorption of the vitamin due to the failure of gastric parietal cells to produce intrinsic factor (as in pernicious anemia) or to a loss of activity of the receptor needed for intestinal uptake of the vitamin.5 Nonspecific malabsorption syndromes or gastric resection can also cause vitamin B12 deficiency. The vitamin may be administered orally (for dietary deficiencies), or intramuscularly or deep subcutaneously (for pernicious anemia). [Note Folic acid administration alone reverses the hematologic abnormality and thus masks the B12 deficiency, which can then proceed to severe neurologic dysfunction and disease. Therefore, megaloblastic anemia should not be treated with folic acid alone, but rather with a combination of folate and vitamin B12.] Therapy must be continued for the remainder of the life of a patient suffering from pernicious anemia. There are no known adverse effects of this vitamin. 

Indirect indicators of vitamin B12 deficiency include measurements of the metabolites homocysteine and methylmalonic acid (MMA) in serum and MMA in urine (see the Biochemical Perspectives section). Whereas the serum homocysteine concentration increases during folate or vitamin B12 deficiencies, the serum and urine MMA concentrations increase only in vitamin B12 deficiency. Therefore, MMA determinations can be used to differentiate vitamin B12 deficiency from folate deficiency. The normal concentration of MMA in serum ranges from 0.08 to 0.28 pmol/L. MMA is quantified using gas-liquid chromatography and mass spectrometry. Elevated concentrations of MMA and homocysteine in serum may precede the development of hematological abnormalities and reductions in serum vitamin B12 concentrations. One should be aware that other conditions, including renal in sufficiency and inborn errors of metabolism, can also result in elevated serum levels of MMA. 

Non-response to epoetin alfa therapy should prompt a search for causative factors. These include iron, folate, or vitamin B12 deficiency aluminium intoxication intercurrent infections inflammatory or traumatic episodes occult blood loss haemolysis and bone marrow fibrosis of any origin. 

The cause of megaloblastosis is depressed DNA synthesis, as a result of impaired methylation of dCDP to TDP, catalyzed by thymidylate synthetase, but more or less normal synthesis of RNA. As discussed in Section 10.3.3, thymidylate synthetase uses methylene tetrahydrofolate as the methyl donor it is obvious that folic acid deficiency will result in unpaired thymidylate synthesis. It is less easy to see how vitamin B12 deficiency results in impaired thymidylate synthesis without invoking the methyl folate trap hypothesis (Section 10.3.4.1). The main circulating form of folic acid is methyl-tetrahydrofolate before this can be used for other reactions in tissues, it must be demethylated to yield free folic acid. The only reaction that achieves this is the reaction of methionine synthetase (Section 10.8.1). Thus, vitamin B12 deficiency results in a functional deficiency of folate. 

A number of methods have been developed to permit assessment of folate and vitamin B12 nutritional status and to differentiate between deficiency of the vitamins as a cause of megaloblastic anemia. Obviously, detection of antibodies to intrinsic factor or gastric parietal cells will confirm autoimmune pernicious anemia rather than nutritional deficiency of either vitamin. 

Folale deficiency occurs in pregnancy on a wide scale. The increased utilization of the vitamin by die fetus and related tissues, as well as the secretion in milk during lactation, can place an increased demand on the dietary folates consumed by the mother. Sea ere folate deficiency leads to megaloblastic anemia. This disease, in which the synthesis of red blood cells is impaired, tends to occur with pregnancy in underdeveloped countries, but usually not in North America or Europe, Goat s milk is a poor source of folate and vitamin Bjj. Ovcrrchancc on goal s milk as a source of food for infants can result in a deficiency in these vitamins and in anemia. 

Chronic overdrinking or binge-drinking alcoholism causes deficiencies of folate, thiamine, pyridoxine, vitamin A, and zinc, the combination of which causes multiple risks for disease, but mostly for cancer. 

Iron deficiency is the most common cause of resistance to erythropoietic therapy. Evaluation and treatment of iron deficiency should occur prior to initiation of erythropoietic therapy as previously discussed (see Figs. 44—1 and 44—2). Inflammation (localized or systemic infection, active inflammatory disease, or surgical trauma) is associated with defective iron utilization known as reticuloendothelial block. Reticuloendothelial block is characterized by a reduction in iron delivery from body stores to the bone marrow, and is generally refractory to iron therapy. Failure to respond to erythropoietic therapy requires evaluation of other factors causing resistance, such as infection, inflammation, chronic blood loss, aluminum toxicity, hemoglobinopathies, malnutrition, and hyperparathyroidism. Erythropoietic therapy may be continued in the infected or postoperative patient, although increased doses are often required to maintain or slow the rate of decline in Hgb/Hct. Deficiencies in folate and vitamin Bi2 should also be considered as potential causes of resistance to erythropoietic therapy, as both are essential for optimal erythropoiesis. Patients on hemodialysis or peritoneal dialysis should be routinely... 

Because of the close interrelationship between the vitamins, patients with deficiencies of either folate or vitamin exhibit similar symptoms. Which of the following tests would best help distinguish between a folate and vitamin Bj deficiency ... 

Although many of these patients had either a diet poor in folate or malab-sorbed the vitamin, a number appeared to have an increased demand suggesting an abnormality in the metabolic pathway of the vitamin. The role of folate in neurological function is not clear folate is important in DNA synthesis, but little DNA synthesis takes place in nervous tissue. There is a requirement for folate in RNA synthesis and it may be here that a deficiency of folate is able to exert its neurological efiect. 

Jean Ann Tonich developed a folate deficiency and is on the verge of devel-j oping a cobalamin (vitamin B12) deficiency as a consequence of prolonged moderately severe malnutrition related to chronic alcoholism. Before folate therapy is started, the physician must ascertain that the megaloblastic anemia is not caused by a pure B12 deficiency or a combined deficiency of folate and B12. 

When the body does not have sufficient red cells, the patient is said to be anemic. Anemia can result from many causes. Nutritional deficiencies of iron, folate, or vitamin B12 prevent the formation of adequate numbers of red cells. Mutations in the genes that encode red cell metabolic enzymes, membrane structural proteins, and globins cause hereditary anemias. The appearance of red cells on a blood smear frequently provides clues to the cause of an anemia. Because the mutations that give rise to hereditary anemias also provide some protection against malaria, hereditary anemias are some of the most common genetic diseases known. 

Megaloblastic anemia A deficiency in serum hemoglobin and red blood cells (erythrocytes) in which the erythrocytes are abnormally large. This type of anemia is caused by folate or vitamin B, deficiency. 

As mentioned, some patients have documented deficiencies of several vitamins. Indeed, isolated clinically significant deficiency of a single vitamin is probably rare. Yet the import of multiple deficiencies is not always clear. Even for the best recognized avitaminoses, such as pellagra or the Wernicke-Korsakoff syndrome, defects in cognition are attributable to lack of more than just the one classically implicated vitamin. Deficiency of multiple water soluble vitamins pertains especially to alcoholics, to the elderly, and to severely ill hospitalized patients. For example, low folate stores, combined with inadequate niacin and thiamine, probably contribute to the chronic memory disorder of alcoholism. 

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. 

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