Folic acid anemia

Macrocytic or magaloblastic anemia is caused by disturbances of DNA synthesis. It occurs, for example, in both folic acid and vitamin B12 deficiencies. Hematopoesis is slowed down due to reduced DNA synthesis and a reduced number of abnormally large (macrocytic) and hemaglobin-rich (hyperchromic) erythrocytes is released. 

It is recommended that women of childbearing age take 400 pg/d synthetic folic acid as a supplement in order to reduce the risk of neural tube defects of the embryo when they later become pregnant (periconcep-tional folic acid supplementation) [2]. When supplementing folic acid, it should be considered that this vitamin can mask the simultaneous presence of vitamin B12 deficiency. The typical symptom of vitamin B12 deficiency, megaloblastic (= macrocytic) anemia, will be reduced by high doses of folic acid, yet the nervous system will - in the long run - be irreversibly damaged (= funicular myelitis) when vitamin B12 is not provided as well. 

The anemias discussed in this chapter include iron deficiency anemia, anemia in patients witii chronic renal disease pernicious anemia, and anemia resulting from a folic acid deficiency. Table 45-1 defines these anemias. Drugp used in treatment of anemia are summarized in die Summary Drug Table Drugp Used in die Treatment of Anemia. 

Anemias, reductions in the number of red blood cells or of hemoglobin in the blood, can reflect impaired synthesis of hemoglobin (eg, in iron deficiency Chapter 51) or impaired production of erythrocytes (eg, in folic acid or vitamin Bjj deficiency Chapter 45). Diagnosis of anemias begins with spectroscopic measurement of blood hemoglobin levels. 

The water-soluble vitamins comprise the B complex and vitamin C and function as enzyme cofactors. Fofic acid acts as a carrier of one-carbon units. Deficiency of a single vitamin of the B complex is rare, since poor diets are most often associated with multiple deficiency states. Nevertheless, specific syndromes are characteristic of deficiencies of individual vitamins, eg, beriberi (thiamin) cheilosis, glossitis, seborrhea (riboflavin) pellagra (niacin) peripheral neuritis (pyridoxine) megaloblastic anemia, methyhnalonic aciduria, and pernicious anemia (vitamin Bjj) and megaloblastic anemia (folic acid). Vitamin C deficiency leads to scurvy. 

Folic acid Coenzyme in transfer of one-carbon fragments Megaloblastic anemia... 

B,2 Cobalamin Coenzyme in transfer of one-carbon fragments and metabolism of folic acid Pernicious anemia = megaloblastic anemia with degeneration of the spinal cord... 

Pernicious anemia arises when vitamin B,2 deficiency blocks the metabohsm of folic acid, leading to functional folate deficiency. This impairs erythropoiesis, causing immature precursors of erythrocytes to be released into the circulation (megaloblastic anemia). The commonest cause of pernicious anemia is failure of the absorption of vitamin B,2 rather than dietary deficiency. This can be due to failure of intrinsic factor secretion caused by autoimmune disease of parietal cells or to generation of anti-intrinsic factor antibodies. 

Folic acid deficiency is also related to megaloblastic anemia. Tetrahydrobiopterin is a co-factor for phenylalanine, tyrosine, and tryptophane hydroxilases — enzymes... 

Explain the optimal use of folic acid and vitamin B12 in patients with macrocytic anemia. 

The underlying cause of anemia (e.g., blood loss iron, folic acid, or B12 deficiency or chronic disease) must be determined and used to guide therapy. 

Anemia from vitamin B12 or folic acid deficiency is treated effectively by replacing the missing nutrient. 

A decrease in erythrocyte production can be multifactorial. A deficiency in nutrients (such as iron, vitamin B12, and folic acid) is a common cause that often is easily treatable. In addition, patients with cancer and CKD are at risk for developing a hypoproductive anemia. Furthermore, patients with chronic immune-related diseases (such as rheumatoid arthritis and systemic lupus erythematosus) can develop anemia as a complication of their disease. Anemia related to these chronic inflammatory conditions is typically termed anemia of chronic disease. 

The underlying cause of anemia (e.g., blood loss iron, folic acid, or vitamin B12 deficiency or chronic disease) must be determined and used to guide therapy. As discussed previously, patients should be evaluated initially based on laboratory parameters to determine the etiology of the anemia (see Fig. 63-3). Subsequently, the appropriate pharmacologic treatment should be initiated based on the cause of anemia. 

Other than transfusion, nonpharmacologic therapy plays a limited role in the management of anemia. Certainly, some causes of anemia can be attributed to diets poor in iron, folic acid, or vitamin B12. However, in the United States, nutrient-poor diets are rarely the sole cause of anemia in a patient. Therefore, ingesting a diet that is rich in iron, folic acid, or vitamin B12 should be encouraged but should not be the only... 

Anemia from vitamin BI2 or folic acid deficiency is treated effectively by replacing the missing nutrient. Both folic acid and vitamin B12 are essential for erythrocyte production and maturation. Replacing these factors allows for normal DNA synthesis and, consequently, normal erythropoiesis. 

Patients typically present by 6-12 months with severe developmental retardation, convulsions, microcephaly and homocysteinemia (=50pmol/l) with hypomethioninemia (<20 pmol/1). A few individuals have had psychiatric disturbances. The blood concentration of vitamin B12 is normal, and, unlike individuals with defects of cobalamin metabolism, these patients manifest neither anemia nor methylmalonic aciduria. The blood folic acid level is usually low. 

Methotrexate, an antimetabolite, is indicated for moderate to severe psoriasis. It is particularly beneficial for psoriatic arthritis. It is also indicated for patients refractory to topical or UV therapy. Methotrexate can be administered orally, subcutaneously, or intramuscularly. The starting dose is 7.5 to 15 mg per week, increased incrementally by 2.5 mg every 2 to 4 weeks until response maximal doses are approximately 25 mg/wk. Adverse effects include nausea, vomiting, mucosal ulceration, stomatitis, malaise, headache, macrocytic anemia, and hepatic and pulmonary toxicity. Nausea and macrocytic anemia can be ameliorated by giving oral folic acid 1 to 5 mg/day. Methotrexate should be avoided in patients with active infections and in those with liver disease. It is contraindicated in pregnancy because it is teratogenic. 

Anemia may be a common problem where there is significant blood loss from the GI tract. When the patient can consume oral medication, ferrous sulfate should be administered. Vitamin B12 or folic acid may also be required. 

Macrocytic anemias Megaloblastic anemias Vitamin B12 deficiency Folic acid deficiency anemia Microcytic hypochromic anemias Iron-deficiency anemia Genetic anomaly Sickle cell anemia Thalassemia... 

The chemistry, metabolism, and clinical importance of folic acid have been the subject of many excellent reviews (A7, Gil, H14, H20, Rl). Folic acid deficiency leads to a macrocytic anemia and leucopenia. These symptoms are due to inadequate synthesis of nucleic acid. The synthesis of purine bases and of thymine, required for nucleic acid synthesis, is impaired in folic acid deficiency. Detection of folic acid activity in biologic fluids and tissues is of the utmost importance it distinguishes between the various anemias, e.g., those due to vitamin Bi2 or folic acid deficiency. Because morphology of the abnormal red cell does not help in diagnosing vitamin deficiency, one must rely on assay methods for differential diagnosis. Treatment of pernicious anemia with folic acid has led to subacute combined degeneration of the spinal cord despite... 

A modification of the above serum folic assay method was recently described (W4). The investigators confirmed the validity of this technique as a practical means of differentiating patients with folic acid from vitamin B12 megaloblastic anemias. Another modification of this method was also described (C4). These investigators reduced the over-all sensitivity by high serum dilutions and thus made the assay, as they used it, valueless as a diagnostic tool. 

There is, moreover, the field of hypervitaminoses, which has been explored for the fat-soluble vitamins, but hardly touched in the water-soluble vitamins. The production of combined system disease by folic acid therapy of pernicious anemia belongs to this group, but many more instances wait to be recognized. The indiscriminate use of polyvitamin preparations by poorly informed clinicians is bound to mask such states and to delay their discovery. Also, the use of flushing doses of vitamins in diagnostic tests may cause acute hypervitaminoses. 

A vitamin is often the etiological center of a disease as vitamin Bi2 and folic acid in macrocytic anemias. Here, because of the obvious implications for diagnosis and therapy the determination of the nucleo-genic vitamins, Bi2 and folic acid, is imperative in the routine of clinical hematology. 

R12. Ross, J. F., Belding, H. W., and Paegel, B. L., Development and progression of subacute combined degeneration of spinal cord in patients with pernicious anemia treated with synthetic pteroyl glutamic (folic) acid. Blood 3, 68-90 (1948). 

Medoxomil, molecular formula and structure, 5 153t Mefluidide, 73 43t, 54 Megaloblastic anemia, folic acid and, 25 802... 

In view of the reported growing importance ascribed to folic acid deficiency in the prevention of various disease conditions, such as neural tube defects, megaloblastic anemia, colon cancer, and colorectal cancer, a dissolution requirement is specified for folic acid when it is present in multivitamin-mineral combination products. Currently, the dissolution standard required in the official articles of dietary supplements (including vitamin-mineral combination products) places folic acid outside the index vitamin hierarchy. Therefore, a mandatory dissolution test for folic acid is required that is independent of and in addition to the mandatory index vitamin test for multivitamin preparations containing folic acid. 

The fact that certain human adults or infants develop types of anemia which respond to small doses of folic acid can be interpreted to mean that, for reasons which doubtless have some genetic basis, these individuals have unusually high demands for this vitamin. Presumably they develop the disease when consuming diets that do not induce the disease in others. Folic acid needs are (for one reason or another) highly variable from individual to individual among patients as is shown by the fact that many patients will respond to as little as 0.5 mg. folic acid per day, whereas others will not respond at all... 

Enzymes dependent on folic acid as coenzyme include participants in the synthesis of thymine, an essential component of DNA, and methionine, a common amino acid in proteins, among other important metabolites. A deficiency of folic acid results in the disease megaloblastic anemia. 

Cell multiplication is inhibited because DNA synthesis is insufficient. This occurs in deficiencies of vitamin Bu or folic acid (macrocytic hyperchromic anemia). 2. Hemoglobin synthesis is impaired. This situation arises in iron deficiency, since Fe + is a constituent of hemoglobin (microcytic hypochromic anemia). 

Folate, the anion of folic acid, is made up of three different components—a pteridine derivative, 4-aminobenzoate, and one or more glutamate residues. After reduction to tetrahydrofolate (THF), folate serves as a coenzyme in the Q metabolism (see p. 418). Folate deficiency is relatively common, and leads to disturbances in nucleotide biosynthesis and thus cell proliferation. As the precursors for blood cells divide particularly rapidly, disturbances of the blood picture can occur, with increased amounts of abnormal precursors for megalocytes megaloblastic anemia). Later, general damage ensues as phospholipid... 

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