Factor Folic Acid Deficiency

There is evidence for the existence of at least five compounds having simi- 

Three names are commonly applied to one or more member of this group of compounds the L. casei factor, folic acid and vitamin Bo. 

Stewart, Daft, and Sebrell (68) have presented evidence for the existence in yeast of another substance closely related to the three L. casei factors which have been mentioned. This fourth L. casei factor is active for the rat but has little or no activity for L. casei t or S. lactis R. A concentrate of this material was rendered active for these microorganisms by treatment with acid or alkali. 

Keresztesy, Rickes, and Stokes (69) announced the isolation of a substance which was less than 1/100,000 as active for L. casei as for S. lactis. 

This compound, called factor SLR, is inactive for the rat (70) and chick (71) which differentiates it sharply from the other five substances we have mentioned. Stokes, Keresztesy, and Foster (72) have presented evidence which indicates that S. lactis and all other strains of lactic acid bacteria which can utilize factor SLR, are able to do so because they can convert it to one of the L. casei factors or a similar active compound. 

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

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. 

With so many causes of deficiency as just delineated, obviously replacement measures must be matched against ihe causes. A primary objective, where feasible, of course, is to remove or alleviate the causative factors. Also, where Ihere are no contraindication factors, folic acid can be administered in therapeutic dosages. Very small dosages (I mg orally per day) can often be effective. 

Iron toxicity can be expected if the amount of free iron released into the plasma exceeds the plasma iron-binding capacity. This is more likely to occur when using iron sorbitol-citric acid complex (iron sorbitex), since the iron is less firmly bound than with iron dextran. Several conditions associated with low iron-binding capacity, such as malnutrition (kwashiorkor, malnutrition syndrome) and previous or simultaneous oral iron therapy appear to predispose to the development of these toxic reactions. In addition, folic acid deficiency has been reported to be a predisposing factor (SED-9, 516), the likely mechanism being altered iron utilization secondary to folic acid deficiency, which results in an increased saturation of ironbinding capacity. 

Cobalmin Deficiency. Pernicious anemia is the disease associated with vitamin Bi2 deficiency. It is usually caused by the inability to produce intrinsic factor. Indeed, many times the vitamin must be administered by injection. The blood picture, a megaloblastic anemia, is indistinguishable from that caused by folic acid deficiency. Indeed folic acid supplements can mask the blood picture. This is illustrated in Fig. 8.53. Removal of ad-enosyl cobalamin eliminates the regeneration of tetrahydrofolate during the methylation of homocysteine to methionine. Folic acid supplements provide a fresh source of tetrahydrofolate coenzymes. DNA synthesis can continue and new erythrocytes form. Excess folic acid also may compete for the available vitamin, further exacerbating vitamin deficiency. 

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. ... 

Paresthesias of the hands and feet are symptoms of vitamin deficiency, not of folic acid deficiency. The lack of neurological symptoms is the differentiating factor used to diagnosis folic acid deficiency because the anemias share most other symptoms. 

Immature red blood cells contain free PROTO. The level of PROTO in the circulating erythrocytes is affected by a number of factors. In iron deficiency, or in anemia following hemorrhage, a high erythrocyte protoporphyrin (EP) is found of 20Q-400 itg per 100 cc. of erythrocytes as contrasted to normal values of 20-40 fig. EP is found to be high also in anemias of infectious nephritis and leukemia. It is low in pyridoxine and folic acid deficiencies (see 5-AL formation) (ISO). In acute lead poisoning of rabbits the EP is 500 fig. In phenylhydrazine poisoning the EP is 300 fig and COPRO is increased also (131). 

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. 

Anaemia often becomes a characteristic feature of several chronic diseases, such as rheumatoid arthritis. In most instances this can be linked to lower than normal endogenous serum EPO levels (although in some cases a deficiency of iron or folic acid can also represent a contributory factor). Several small clinical trials have confirmed that administration of EPO increases haematocrit and serum haemoglobin levels in patients suffering from rheumatoid arthritis. A satisfactory response in some patients, however, required a high-dose therapy that could render this therapeutic approach unattractive from a cost benefit perspective. 

There is a possibility that a partial deficiency of some vitamins (especially vitamin B12 and folic acid) impairs the activity of key enzymes in the brain which might be one factor in the development of senile dementia and even Alzheimer s disease (see above for discussion of homocysteine in this context). 

In a totally different field, studies were being carried out on children who had a deficiency of methionine synthase and an impaired ability to convert homocysteine to methionine, so that they had increased blood levels of homocysteine. It was noted that these children had an increased incidence of thrombosis in cerebral and coronary arteries. This led to a study which eventually showed that an increased level of homocysteine was a risk factor for coronary artery disease in adults. Since methionine synthase requires the vitamins, folic acid and B12, for its catalytic activity, it has been suggested that an increased intake of these vitamins could encourage the conversion of homocysteine to methionine and hence decrease the plasma level of homocysteine. This is particularly the case for the elderly who are undernourished (see Chapter 15 for a discussion of nutrition in the elderly). 

Dietary deficiency anaemia, which is due to deficient supply of various factors e.g. iron, folic acid, vitamin vitamin C and pyridoxine which are essential for normal blood formation. 

Studies on growth factors required by certain microorganisms, for example Streptococcus faecalis and Lactobacillus casei, and of their relevance in animal nutrition, led to the isolation and characterization of folic acid, pteroylglutamic acid (104), the structure of which was determined in 1946. It is an essential vitamin for man and together with vitamin B12 it is involved in the development of blood cells. Deficiency causes macrocytic anaemia. Many microorganisms do not use exogenous folic acid, but synthesize their own, and some... 

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