Folate metabolism erythrocytes

There have been other single reports of megaloblastic anemia associated with an apparent abnormality of folate metabolism. One child had a normal serum folate of 6 p,g/liter, an erythrocyte folate of 1480 p.g/liter, and a megaloblastic anemia which responded to treatment with folic acid (VI). Lampkin (Lll) described two sisters with a severe megaloblastic anemia and normal vitamin 6 2 folate levels. Absorption of vitamin 6, 2 normal and both patients excreted an increased amount of formiminoglutamic acid. It was thought that they required both vitamin B 2 and folate to restore normoblastic hemopoiesis. 

Little is known about other aspects of folate metabolism, such as the factors that determine plasma clearance, in either normal subjects or users of oral contraceptive steroids. As described earlier, maximum serum folate concentrations after oral folate polyglutamate are lower in contraceptive users than in nonusers, when subjects are not presaturated (S19). This may be due to increased clearance from plasma, because poor absorption was not found. Stephens et al. (S19) felt that this was probably not due to tissue folate depletion because there was no correlation with initial fasting serum folate concentrations. However, erythrocyte folate concentrations were not measured and might have been a better index of tissue saturation with the vitamin. 

It is evident, therefore, that the 2,4-diaminopyrimidines, like pyrimethamine and trimethoprim, the dihydrotriazines like proguanil (in its active metabolite form), the 2,4-diaminopteridines, and methotrexate, inhibit dihydrofolate reductase. Their selective toxicity to plasmodia may be due to a combination of greater binding to the parasite enzyme and to their selective uptake by parasitised erythrocytes. However, a new antifolic mode of action has recently been proposed for compounds like tetrahydrohomopteroic acid [288], which may inhibit folate metabolism by an action on the feedback... 

There are several vitamin Bg-responsive inborn errors of metabolism that include (1) cases of infantile convulsions in which the apoenzyme for glutamate decarboxylase has a poor affinity for the coenzyme (2) a type of chronic anemia in which the number but not morphological abnormality of erythrocytes is improved by pyridoxine supplementation (3) xanthurenic aciduria in which affinity of the mutant kynureninase for PLP is decreased (4) primary cystathion-inuria caused by similarly defective cystathionase and (5) homocystinuria in which there is less of the normal cystathionine synthetase. In these cases increased levels (200 to lOOOmg/day) of administered vitamin Bg are required for life. Low vitamin Bg status (together with low vitamin B12 and folate status) in humans has been linked to hyperho-mocysteinemia and as an independent risk factor for cardiovascular disease. ... 

Folate status may be reliably assessed by direct measurement of serum and erythrocyte or whole blood concentrations, and its metabolic function as coen2yme assessed by metabolite concentrations, such as plasma homocysteine (see Chapters 20 and 26). Serum folate concentrations are considered indicative of recent intake and not of tissue stores, but serial measurements have been used to confirm adequate intake. Whole blood or erythrocyte folate concentrations are more indicative of tissue stores and have been shown to have a moderate correlation with liver folate concentrations taken through a biopsy. Because folate is taken up only by the developing erythrocyte in the bone marrow and not by the mature cell, erythrocyte concentrations reflect folate status over the 120-day lifespan of the ceU. Urine folate excretion is not considered to be a sensitive indicator of folate status. ... 

What appeared to be a new inborn error of metabolism was described by Branda in 1978 (B19). The patient was a young man who came from a family in which hematological disease had contributed to, or caused the death of 18 of 34 affected members of the family. He was found to have a severe anemia and an aplastic bone marrow and required regular transfusions. A further bone marrow biopsy 2 years later showed continuing severe aplasia but a megaloblastic change was noted in the few remaining erythrocyte precursors. His serum vitamin normal but his serum folate was minimally... 

One patient has been found with this deficiency (All). Hie patient, an infant, was mentally retarded, had a megaloblastic anemia and abnormally high levels of serum and erythrocyte folate. In spite of the high serum folate concentration there was a marked rise in the reticulocyte count when the patient was treated with folate. It was thought that the patient had impaired utilization of -methyltetrahydrofolate. Assay of liver W -methyltetrahy-drofolate transferase showed it to be reduced. It was suggested that folate accumulated at the N -methyltetrahydrofolate block and could therefore not be further utilized. Treatment with pteroylglutamic acid provided a means of producing active folate up to the point of the block. Unfortunately this patient was also treated with pyridoxine, and it is not clear which vitamin was responsible for the reticulocyte response. Further studies are required to determine the precise nature of this metabolic disorder. 

Table 28.3 Homocysteine metabolism parameters in preeclampsia. Data expressed as median (interquartile range). Serum and erythrocyte folate levels not reported because these were within relevant reference interval in both groups. Data are from a study by our group.

Nutrition The effect of warfarin therapy for 6 months on folate status has been studied in 114 patients, using measurements of erythrocyte folate and 5-methyltetrahydro-folate and plasma folate, total homocysteine, phylloquinone, vitamin B12, and methylmalonic acid [ll. There were significant falls in total erythrocyte folate and 5-methyltetrahydrofolate and a concurrent increase in plasma phylloquinone, attributed to altered vitamin K metabolism. 

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