Clinical and experimental studies on folic acid deficiency due to anticonvulsants. 2. Investigations on patients receiving anticonvulsants and experimental study on the effect of diphenylhydantoin on the absorption of folic acid in rats

A high incidence of subnormal serum folic acid levels was observed in 48 patients receiving anticonvulsants (75 %). In peripheral blood, macrocytosis was detected in 46 % and an increase of hypersegmented neutrophils was also seen in 24 % of the patients. Correlation existed between these signs and low serum folate levels. The growth response of Lactobacillus casei and L. leichmannii was not suppressed by the addition of various anticonvulsants to the medium of the bioassay systems. Administration of 5 mg of folic acid for a month corrected macrocytosis and an increase of hypersegmented neutrophils significantly. Folic acid supply also decreased mean diameters of the nuclei of oral epithelial cells significantly. It is concluded that subclinical folic acid deficiency is common among the patients receiving anticonvulsants. Absorption of 3H.folic acid from the small intestine of rats was inhibited by large dose of diphenylhydantoin (20 mg) not by 5 mg. This fact suggests that in patients on diphenylhydantoin, the quantity balance of folic acid and diphenylhydantoin in the intestine regulates the absorption of folic acid.</p

Megaloblastic anemia in Japan

Since 1903, 744 cases of megaloblastic anemia have been reported in Japan: 490 cases of pernicious anemia; 95 cases associated with pregnancy; 66 cases after gastrectomy; 22 cases of megaloblastic anemia of infants; 21 cases of folic acid deficiency other than pregnancy and 19 cases of vitamin B12 malabsorption after ileal resection. It is generally agreed among hematologists in Japan that pernicious anemia is relatively rare, as in other Asian countries. The diagnosis of pernicious anemia in Japan is usually made by stained marrow films, radioisotopic assay of serum vitamin B12, Schilling test and good response to vitamin B12 therapy. Serum folate level, intrinsic factor or its antibody, methylmalonic acid excretion, formiminoglutamic acid excretion and deoxyuridine suppression test are performed only at a small number of laboratories. The drugs of choice are hydroxocobalamin, deoxyadenosylcobalamin and methylcobalamin. Cyanocobalamin has nearly disappeared from commercial sources in Japan. Vitamin B12 administration is common in patients with neurological disorders. Megaloblastic anemia due to folic acid deficiency is extremely rare in Japan. Low serum folate levels are frequently observed among patients receiving anticonvulsants or in pregnant women, but in such samples megaloblastic anemia is almost never detected. The folic acid content of hospital diets indicates that satisfactory amounts of folate are taken in Japan. The intake of folic acid from rice is well over the minimum daily requirement of folate. Other factors in folic acid deficiency, such as food taboos, severe alcoholism and malabsorption syndrome are not frequently found in Japanese. The inadequate intake of folate was the critical factor in most reported cases.</p

Clinical and experimental studies on folic acid deficiency due to anticonvulsants. I. Clinical and nutritional study on megalobastic anemia due to anticonvulsants

Two cases of megaloblastic anemia associated with anticonvulsant drugs were studied. Both cases were inpatients of psychiatric hospitals and had quite inadequate intakes of food. The former had lung tuber. culosis and the second had febril illness before the manifestation of anemia. Multiple examinations including bone marrow smears, serum iron levels, vitamin B12 levels, estimation of urinary formiminoglutamic acid after histidine loading and folic acid tolerance test revealed that this anemia was due to folic acid deficiency. Complete hematological responses were ob3erved with injection of folic acid. Retrospective nutritional study on the second case was carried out. The study revealed that folic acid content of the diet of this hospital was 152 fl.g of free folate and 522 fl.g of total folate. The folic acid mtake of the patient was about 80 /1.g of free folate and 280 l1.g of total folate daily during a month before the manifestation of megaloblatic anemia. Importance of additional factors for the development of megaloblastic anemia in patients receiving anticonvulsants was discussed and it was concluded that most important factor was nutritional deficiency of folic acid.</p

Folic acid metabolism in Rauscher murine leukemia and effect of methotrexate on the blood picture

Folic acid contents of plasma, whole blood, liver and spleen in Rauscher leukemic mice were estimated. Plasma and liver folate in the leukemic mice was lower than that of normal mice, suggesting that folic acid was deficient in Rauscher leukemia. Folic acid contents in whole blood and spleen were even higher in the leukemic mice than those in normal mice. Clearance study by injecting folic acid intravenously into leukemic mice showed faster disappearance of folic acid from the circulating blood, suggesting that folic acid demand of Rauscher leukemia is increased. Methotrexate administered shortly after inoculation of the virus did not prevent Rauscher leukemia. But anemia, reticulocytosis and erythroblastosis, which are commonly seen 3-4 weeks later in leukemic controls, were not marked as compared with controls. It can be concluded that the requirement of folic acid is greater in Rauscher leukemia than in controls, and methotrexate is effective for preventing hematological changes commonly seen in this type of leukemias.</p

Anemia in the elderly patients with special reference to folic acid status

To investigate the role of folic acid deficiency in the pathogenesis of anemia in the elderly, hematological examinationa and assays of serum iron, vitamin B12 and folate were carried out on the 86 elderly patients admitted to a home for the aged. Means of red blood cell counts, hemoglobin levels and hematocrit were 385.3 x 10(4)/mm3, 12g/dl and 36%, respectively. These levels were lower than any other report in Japan. Anemia was detected in 23 out of 86 patients. Judging from mean corposcular volume and mean corposcular hemoglobin, most of them were normocytic and normochromic. Although low serum levels of iron and folate were rather frequently observed, the results on hematological examinations suggest that deficiency of these factors alone is not the cause of the anemia in the elderly patients. Rapid clearance of 5-methyl-tetrahydrofolic acid and increased excretion of formiminoglutamic acid after histidine loading were revealed in some of those who had subnormal serum folate levels. Therefore, supplementation of folic acid is recommended to those who had poor dietary intake.</p

Deoxyuridine suppression test: a comparison of two methods and effect of thymidine on the incorporation of 3H-deoxyuridine into DNA in human bone marrow cells

Deoxyuridine suppression tests have been performed by two different methods of six normoblastic and eight megaloblastic marrows. A good correlation was obtained between the results by the modified and the original methods. The simplified method was found to be applicable for a clinical purpose to diagnose megaloblastosis in the marrow. Uptake of 3H-deoxyuridine into DNA and effect of various concentrations of thymidine was studied on five normoblastic and six megaloblastic marrows. In megaloblastic marrows, a greater amount of thymidine was required to obtain the same rate of suppression of 3H-deoxyuridine incorporation into DNA than in normoblastic marrows. Impairment of thymidine incorporation into DNA in megaloblastic marrows was not revealed. Therefore, lower rate of suppression of 3H-deoxyuridine by thymidine in megaloblastic marrows may be due to impairment of the incorporation of deoxyuridine before the addition of thymidine.</p

Immune suppression in HTLV-I carriers: a predictive sign of adult T-cell leukemia.

Suppression of the cellular immune system appears to be a prerequisite for the manifestation of adult T-cell leukemia (ATL). In other words, ATL will develop when impairment of the immune system is caused by the infection of human T-lymphotropic virus type I (HTLV-I). This defect of immune surveillance against virus-infected cells may be a result of the impairment of the function of cytotoxic T-cells (CTLs) specific for the HTLV-I-infected cells. The manifestation of ATL could be predicted by examining the function of CTLs in HTLV-I carriers. A new strategy of prevention and therapy for ATL would include an attempt to restore and fortify the CTL function of the host.</p

Hematological studies on iron- and folate-requirements in pregnancy

Hematological changes and serum iron, vitamin B12 and folate levels after administration of iron plus folic acid were com· pared with changes and levels after supplement of iron alone in 100 pregnant women. No hematological benefits by adding folic acid was revealed. It is concluded that folic acid deficiency in pregnant women is mild and routine supplementation of folic acid is not necessary except for proved cases of folate deficiency. As to the reason why folic acid deficiency is so mild and megaloblastic anemia is so rare in Japan, uniformity of dietary habits, i. e. boiled rice as basic food, was discussed.</p

Cryptococcal pleural effusion in an HTLV-I carrier with Waldenstroem's macroglobulinemia.

A 70-year-old woman with Waldenstroem's macroglobulinemia developed bilateral pleural effusions due to Cryptococcus neoformans. She was found to be a carrier of HTLV-I. It is speculated that the opportunistic infection occurred as the result of an impaired cellular immunity secondary to HTLV-I infection.</p