Deficiency of Folic Acid and Vitamin

Poston (1984) showed that, in isolated rat tissues, about 5% of the catabolic flux of leucine was by way of timinomutase action to yield / -leucine, and then isobutyryl CoA, with the remainder provided by the more conventional O -transamination pathway leading to the formation of isoveileryl CoA. In patients suffering from vittimin B12 deficiency, there is an elevation of plasma / -leucine, suggesting that the aminomutase may act to metabolize / -leucine arising from intestinal bacteria, rather than as a pathway for leucine catabolism. 

Both vittimin B12 tmd folate deficiencies are tissociated with psychiatric illness. Folate deficiency is most commonly associated with depression, whereas cognitive impairment and dementia ene seen in about 25% of patients with either deficiency (Bottiglieri, 1996 Green emd Miller, 1999). Herbert (1962) noted insomnia, forgetfulness, and irritability during the development of self-imposed folate deficiency, which responded well to the administration of the vitcimin. 

Folate deficiency is relatively common 8% to 10% of the population of developed countries have low or meugintd folate stores. By contrast, dieteuy deficiency of vitamin B12 is reue, and deficiency is most often the result of impaired absorption (Section 10.7.1). 

Dietcu y deficiency of vitamin B12 does occur, rtnely, in strict vegetcu iems, because there are no plemt foods that tire sources of vittunin B12. The smadl amounts that have been reported in some plants emd algae ene almost certainly from bacterial contamination. 

Deficiency of either folic acid or vitamin B12 results in a clinically similar megaloblastic anemia because of the neurological damage that accompanies the megaloblastic anemia of vitamin B12 deficiency, the condition is generally known as pernicious anemia. Suhoptimal folate status is also associated with increased incidence of neural tube defects (Section 10.9.4), hyperhomocys-teinemia leading to increased risk of cardiovascular disease (Section 10.3.4.2), and undermethylation of DNAleadingto increased cancerrisk (Section 10.9.5). 

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Deficiencies of folic acid and vitamin B1 are relatively common. Whenever macrocytic anemia is present, evaluation of these two vitamins is necessary 10 determine the cause of the condition, The standard method of measuring folic acid has been the microbiological assay (Bailey et al.. 19821. which can be used to measure folic acid in serum, blood, tissues, and foods. Improved high performance liquid chromatography (HPLC) methods have... 

Tropical sprue, caused by a deficiency of folic acid and vitamin B-12. 

High doses of folic acid and vitamin B12 increase the reticulocyte count. Use of either of these vitamins can therefore mask a deficiency of the other (SEDA 17, 440). If anemia due to deficiency of either of these nutrients is suspected, serum concentrations of both vitamin Bi2 and folic acid should be assessed (28). 

Mr. Veere s malnourished state was reflected in his admission laboratory profile. The results of hematologic studies were consistent with an iron deficiency anemia complicated by low levels of folic acid and vitamin Bi2, two vitamins that can affect the development of normal red blood cells. His low serum albumin level was caused by insufficient protein intake and a shortage of essential amino acids, which result in a reduced ability to synthesize body proteins. The psychiatrist requested a consultation with a hospital dietician to evaluate the extent of Mr. Veere s marasmus (malnutrition caused by a deficiency of both protein and total calories) as well as his vitamin and mineral deficiencies. 

As with phenobarbital, serious toxicity for primidone is rare, although it may cause disabling sedation. Irritability, and decreased mental functioning In a number of persons. Ataxia, dysphoria, idiosyncratic rash, leukopenia, agranulocytosis, lymphadenopathy, hepatitis, and a systemic lupus erythematosus-like syndrome have been reported adverse effects for primidone. Deficiencies of folic acid and of vitamins D and K are possible with long-term therapy of primidone, as Is a folate-responsive megaloblastic anemia. Measurement of the complete blood cell count should be performed at 6-month intervals (40). 

In most instances the primary deficiency is in folic acid, or there may be a combined deficiency of folic acid and of ascorbic acid (May et al., 1950a Zuelzer and Ogden 1946a,b Zuelzer, 1946, 1947 Aldrich and Nelson, 1947). The citrovorum factor was effective in doses as small as 75fig. daily (Woodruff et al., 1951). As might be expected, some infants failed to respond to vitamin B12 examples are given by Luhby and Wheeler (1949) and Woodruff et al. (1949, case 3). 

Since vitamin B12 may fail, the proper course in treating infants with megaloblastic anemia is probably to give foUc acid, which is always effective. As there may be an associated deficiency of ascorbic acid and vitamin B12, these agents may be administered too (May et al., 1950a). The possible role of these two substances in the conversion of folic acid to citrovorum factor is discussed on pages 186 and 188. 

There are two major types of nutritional megaloblastic anemia one is due to a deficiency of folic acid, and the other is due to a deficiency of vitamin B-12. 

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. 

Deficiencies in nutrients such as folic acid and vitamin B12 may hinder this process of erythrocyte maturation.4,5 Folic acid and vitamin B12 are important nutrients required for the formation of DNA. In a setting where these nutrients are decreased, DNA synthesis is inhibited, and consequently, erythrocyte maturation also is inhibited.4,5 Poor diet can be a contributor to the deficiencies in these... 

Prognosis is more favorable in the pyridoxine-respon-sive patients. Patients who respond to large doses of vitamin B6 (250-500 mg/day for several weeks) have the best prognosis. Efficacy of treatment usually is reflected in a reduction of blood homocystine and methionine to normal or near-normal levels. Since supplementation with pyridoxine can cause a deficiency of folic acid, the latter should be given (2-5 mg daily) at the same time. Any patient receiving pyridoxine should be monitored carefully for any signs of hepatotoxicity and for a peripheral neuropathy (see Ch. 36). 

Folic acid (vitamin Bg) is a conjugate of a pteridine unit, p-aminobenzoic acid, and glutamic acid. Deficiency of folic acid leads to anaemia, and it is also standard practice to provide supplementation during pregnancy to reduce the incidence of spina bifida. 

The answer is D. Several vitamin deficiencies can cause anemia due to reduced DNA synthesis in the erythropoietic cells of the bone marrow, especially folic acid and vitamin Bj2 (cobalamin), which are particularly prevalent among elderly patients due to poor diet and reduced absorption. In addition, deficiencies of either folic acid or vitamin Bj2 could produce the megaloblastic anemia seen in this patient. However, the absence of neurologic symptoms, a hallmark of vitamin Bj2 deficiency, makes that diagnosis less likely than folic acid deficiency. 

Normal blood levels of vitamin B12 are 2 x 1(T10 M or a little more, but in vegetarians the level may drop to less than one-half this value. A deficiency of folic acid can also cause megaloblastic anemia, and a large excess of folic acid can, to some extent, reverse the anemia of pernicious anemia and mask the disease. 

Examination of the bone marrow, although important, will only confirm that the hemopoiesis is megaloblastic. A deficiency of folic acid will also cause a megaloblastic anemia and it is not possible to identify the cause on the basis of morphology. A serum assay of both vitamins will usually indicate which is responsible. If the patient is vitamin B12 deficient, the next step is to carry out a vitamin B12 absorption test to confirm that the deficiency is due to a lack of intrinsic factor. Preferably this should not be done until the patient s vitamin B12 and hemoglobin levels have returned to normal, since the gastric and intestinal cells are also affected by a lack of vitamin B12 aborption may be less than optimal if it is attempted too early. Patients with pernicious anemia also have a histamine-fast achlorhydria and gastric atrophy. The disease appears to have an autoimmune basis and antibodies to intrinsic factor can be demonstrated in the serum of more than half of affected patients. 

On the day of admission, the patient had developed a deep venous thrombosis in his right calf, a site not involved in the injury. In investigating the underlying cause of the deep venous thrombosis, serum homocysteine was measured and found to be 17.4 pmol/L (normal is < 14 pmol/I.).To distinguish between folic acid and vitamin B12 deficiencies, a serum methylmalonic acid (MMA) assay was performed it yielded a result of 0.59 pmol/I. MMA (normal is < 0.30 pmol/L). This confirmed the presence of vitamin B12 deficiency, despite a serum B12 concentration that was within the normal range. 

Antibiotics. Long-term administration of antibiotics could lead to vitamin B6 deficiency, If symptoms of peripheral neuropathy develop (numbness and tingling of the extremities), administer vitamin B6. Sulfasalazine can decrease the absorption of folic acid, and trimethoprim can cause folate deficiency, hence the need to administer folic acid if there is evidence of deficiency. Rifampicin can cause disturbances in vitamin D metabolism and lead to osteomalacia. The absorption of tetracyclines can be reduced by calcium, magnesium, iron and zinc, while this antibiotic could also decrease the absorption of these minerals. This effect is probably least with minocycline and is not confirmed with doxycycline. Doses of minerals and antibiotic should be separated by at least 2 hours. The absorption of quinolones is reduced by cationic and anionic supplements. 

Deficiency of folic acid leads to a megaloblastic anaemia because it is necessary for the production of purines and pyrimidines, which are essential precursors of deoxyribonucleic acid (DNA). The megaloblastic marrow of cobalamin deficiency is due to interference with folic acid utilisation and the morphological changes of cobalamin deficiency can be reversed by folic acid. It is vital to realise that folic acid does not provide adequate treatment for pernicious anaemia. Nor does vitamin 3 2 provide adequate treatment for the megaloblastic anaemia of folic acid deficiency, although a partial response may occur because vitamin plays a role in folate metabolism. 

Although requirements for vitamins and trace elements are known in health (Table 30-1), the effects of illness on these requirements are poorly understood and quantified. However, it is now apparent that as an individual develops progressively more severe depletion in vitamin or trace element status, the person passes through a series of stages with biochemical or physiological consequences. The metabolic or physiological penalty of such suboptimal nutritional status is usually not clear, but the assumption remains that the suboptimal metabolism is likely to have detrimental effects (e.g., subclinical deficiency of folic acid is associated with an increase in serum homocysteine concentration, which is an independent risk factor for coronary artery disease—see Chapter 26). Similarly, subclinical deficiency of chromium may be associated with impaired glucose tolerance in certain types of diabetes. 

Because flavin coenzymes are widely distributed in intermediary metabolism, the consequences of deficiency maybe widespread. Because riboflavin coenzymes are involved in the metabohsm of folic acid, pyridoxine, vitamin K, and niacin, deficiency will affect enzyme systems other than those requiring flavin coenzymes. With increasing riboflavin deficiency, tissue concentrations of FMN and FAD fall, as does flavokinase activity, thus further decreasing FMN concentrations. FMN concentrations are decreased proportionally more than FAD concentrations. Decreases in the activities of enzymes requiring FMN generally follow the fall in tissue concentrations, whereas the FAD-dependent enzymes are more variably affected. ... 

Folic acid and vitamin B]2 metabohsm are linked by the reaction that transfers a methyl group from 5-MTHF to cobalamin. In cases of cobalamin deficiency, folate is trapped as 5-MTHF and is metabolically dead. It cannot... 

MCV represents the average volume of RBCs. Cells are said to be macrocytic if they are larger than normal, microcytic if they are smaller than normal, and normocytic if their size falls within normal limits. Folic acid and vitamin B12 deficiency anemias yield macrocytic morphology, whereas iron deficiency and thalassemia are examples of microcytic anemias. A falsely elevated MCV occurs with reticulo-cytosis because reticulocytes are larger than erythrocytes. The MCV is also falsely elevated in the presence of cold agglutinins and hyperglycemia. When IDA (decreased MCV) is accompanied by folate deficiency (increased MCV), failure to understand that the MCV rep-... 

Frenkel EP, Yardley DA. Clinical and laboratory features and sequelae of deficiency of folic acid (folate) and vitamin Bj (cobalamin) in pregnancy and gynecology. Hematol Oncol Clin North Am 2000 14(5) 1079-100. 

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