Skip to main content
NCBI home page
Bulletin of the World Health Organization logoLink to Bulletin of the World Health Organization
. 1963;28(4):517–529.

Folates in megaloblastic anaemia

J Metz
PMCID: PMC2554740  PMID: 13935207

Abstract

The importance of deficiency of the folic acid group of compounds (folates) in the pathogenesis of nutritional anaemias is receiving increasing recognition. There is evidence that the megaloblastic anaemias, due to either vitamin B12 or folate deficiency, may be the cause of widespread morbidity in malnourished populations. It was therefore considered timely to review certain aspects of the role of folates in megaloblastic anaemia, with special reference to the dietary intake in relation to human requirements, and the recognition of folate deficiency in man.

Full text

PDF
517

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. ANDERSON B., BELCHER E. H., CHANARIN I., MOLLIN D. L. The urinary and faecal excretion of radioactivity after oral doses of H3-folic acid. Br J Haematol. 1960 Oct;6:439–455. doi: 10.1111/j.1365-2141.1960.tb06262.x. [DOI] [PubMed] [Google Scholar]
  2. Angier R. B., Boothe J. H., Hutchings B. L., Mowat J. H., Semb J., Stokstad E. L., Subbarow Y., Waller C. W., Cosulich D. B., Fahrenbach M. J., Hultquist M. E., Kuh E., Northey E. H., Seeger D. R., Sickels J. P., Smith J. M., Jr SYNTHESIS OF A COMPOUND IDENTICAL WITH THE L. CASEI FACTOR ISOLATED FROM LIVER. Science. 1945 Aug 31;102(2644):227–228. doi: 10.1126/science.102.2644.227. [DOI] [PubMed] [Google Scholar]
  3. BAKER H., HERBERT V., FRANK O., PASHER I., HUTNER S. H., WASSERMAN L. R., SOBOTKA H. A microbiologic method for detecting folic acid deficiency in man. Clin Chem. 1959 Aug;5(4):275–280. [PubMed] [Google Scholar]
  4. BAKERMAN H. A., SILVERMAN M., DAFT F. S. Influence of succinylsulfathiazole and folic acid on glutamic acid excretion. J Biol Chem. 1951 Jan;188(1):117–123. [PubMed] [Google Scholar]
  5. BALDRIDGE R. C. The metabolism of histidine. II. Effects of folic acid deficiency. J Biol Chem. 1958 Mar;231(1):207–210. [PubMed] [Google Scholar]
  6. CARTWRIGHT G. E., TATTING B. Experimental production of a nutritional macrocytic anemia in swine. Blood. 1949 Apr;4(4):301–323. [PubMed] [Google Scholar]
  7. CHANARIN I., ANDERSON B. B., MOLLIN D. L. The absorption of folic acid. Br J Haematol. 1958 Apr;4(2):156–166. doi: 10.1111/j.1365-2141.1958.tb03846.x. [DOI] [PubMed] [Google Scholar]
  8. CHANARIN I., BENNETT M. C. A spectrophotometric method for estimating formimino-glutamic and urocanic acid. Br Med J. 1962 Jan 6;1(5270):27–29. doi: 10.1136/bmj.1.5270.27. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. CHANARIN I., BENNETT M. C., BERRY V. Urinary excretion of histidine derivatives in megaloblastic anaemia and other conditions and comparison with the folic acid clearance test. J Clin Pathol. 1962 May;15:269–273. doi: 10.1136/jcp.15.3.269. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. CHANARIN I., MACGIBBON B. M., O'SULLIVAN W. J., MOLLIN D. L. Folic-acid deficiency in pregnancy. The pathogenesis of megaloblastic anaemia of pregnancy. Lancet. 1959 Oct 24;2(7104):634–639. doi: 10.1016/s0140-6736(59)91409-6. [DOI] [PubMed] [Google Scholar]
  11. CHANARIN I., MOLLIN D. L., ANDERSON B. B. Folic acid deficiency and the megaloblastic anaemias. Proc R Soc Med. 1958 Sep;51(9):757–763. doi: 10.1177/003591575805100916. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. CHANARIN I., MOLLIN D. L., ANDERSON B. B. The clearance from the plasma of folic acid injected intravenously in normal subjects and patients with megaloblastic anaemia. Br J Haematol. 1958 Oct;4(4):435–446. doi: 10.1111/j.1365-2141.1958.tb06045.x. [DOI] [PubMed] [Google Scholar]
  13. COOPER B. A., LOWENSTEIN L. Evaluation of assessment of folic-acid deficiency by serum folic-acid activity measured with L. casei. Can Med Assoc J. 1961 Oct 28;85:987–988. [PMC free article] [PubMed] [Google Scholar]
  14. COOPERMAN J. M., LUHBY A. L., AVERY C. M. Serum folic acid activity by improved L. casei assay. Proc Soc Exp Biol Med. 1960 Aug-Sep;104:536–539. doi: 10.3181/00379727-104-25900. [DOI] [PubMed] [Google Scholar]
  15. COX E. V., MATTHEWS D. M., MEYNELL M. J., COOKE W. T., GADDIE R. Cyanocobalamin, ascorbic acid and pteroylglutamates in normal and megaloblastic bone marrow. Blood. 1960 Mar;15:376–387. [PubMed] [Google Scholar]
  16. COX E. V., MEYNELL M. J., COOKE W. T., GADDIE R. The folic acid excretion test in the steatorrhea syndrome. Gastroenterology. 1958 Oct;35(4):390–397. [PubMed] [Google Scholar]
  17. DAVIS R. E., ONESTI P. An improved microbiological assay for formiminoglutamic acid. Aust J Exp Biol Med Sci. 1960 Jun;38:239–243. doi: 10.1038/icb.1960.24. [DOI] [PubMed] [Google Scholar]
  18. EBAUGH F. G., Jr, GARDINER R. C., SILVERMAN M. The nature of labile citrovorum factor in human urine. J Biol Chem. 1956 Nov;223(1):259–270. [PubMed] [Google Scholar]
  19. FRANK H. G., GALLANT D. L., TOENNIES G. Blood folic acid activity of normal humans, cancer patients, and noncancer patients; with a few observations on animals. Cancer. 1956 Sep-Oct;9(5):1053–1058. doi: 10.1002/1097-0142(195609/10)9:5<1053::aid-cncr2820090524>3.0.co;2-n. [DOI] [PubMed] [Google Scholar]
  20. GIRDWOOD R. H. A folic-acid excretion test in the investigation of intestinal malabsorption. Lancet. 1953 Jul 11;265(6776):53–60. doi: 10.1016/s0140-6736(53)91084-8. [DOI] [PubMed] [Google Scholar]
  21. GRASBECK R., BJORKSTEN F., NYBERG W. [Formiminoglutamic acid in the urine in folic acid deficiency]. Nord Med. 1961 Sep 28;66:1343–1348. [PubMed] [Google Scholar]
  22. GROSSOWICZ N., ARONOVITCH J., RACHMILEWITZ M., IZAK G., SADOVSKY A., BERCOVICI B. Folic and folinic acid in maternal and foetal blood. Br J Haematol. 1960 Jul;6:296–302. doi: 10.1111/j.1365-2141.1960.tb06246.x. [DOI] [PubMed] [Google Scholar]
  23. GROSSOWICZ N., RACHMILEWITZ M., IZAK G., ZAN S. Determination of folic acid metabolites in normal subjects and in patients with nutritional megaloblastic anemia. Proc Soc Exp Biol Med. 1962 Apr;109:770–773. doi: 10.3181/00379727-109-27332. [DOI] [PubMed] [Google Scholar]
  24. HANSEN H. A., NYSTROM B. Blood folic acid levels and folic acid clearance in geriatric cases. Gerontol Clin (Basel) 1961;3:173–182. doi: 10.1159/000244680. [DOI] [PubMed] [Google Scholar]
  25. HERBERT V., BAKER H., FRANK O., PASHER I., SOBOTKA H., WASSERMAN L. R. The measurement of folic acid activity in serum: a diagnostic aid in the differentiation of the megaloblastic anemias. Blood. 1960 Feb;15:228–235. [PubMed] [Google Scholar]
  26. HERBERT V., LARRABEE A. R., BUCHANAN J. M. Studies on the identification of a folate compound of human serum. J Clin Invest. 1962 May;41:1134–1138. doi: 10.1172/JCI104565. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. HERBERT V., ZALUSKY R. Interrelations of vitamin B12 and folic acid metabolism: folic acid clearance studies. J Clin Invest. 1962 Jun;41:1263–1276. doi: 10.1172/JCI104589. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. HIATT H. H., GOLDSTEIN M., TABOR H. Urinary excretion of formiminoglutamic acid by human subjects after antifolic acid therapy. J Clin Invest. 1958 Jun;37(6):829–832. doi: 10.1172/JCI103671. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. IZAK G., RACHMILEWITZ M., SADOVSKY A., BERCOVICI B., ARONOVITCH J., GROSSOWICZ N. Folic acid metabolites in whole blood and serum in anemia of pregnancy. Am J Clin Nutr. 1961 Jul-Aug;9:473–477. doi: 10.1093/ajcn/9.4.473. [DOI] [PubMed] [Google Scholar]
  30. JANDL J. H., LEAR A. A. The metabolism of folic acid in cirrhosis. Ann Intern Med. 1956 Dec;45(6):1027–1044. doi: 10.7326/0003-4819-45-6-1027. [DOI] [PubMed] [Google Scholar]
  31. JUKES T. H. Assay of compounds with folic acid activity. Methods Biochem Anal. 1955;2:121–151. doi: 10.1002/9780470110188.ch5. [DOI] [PubMed] [Google Scholar]
  32. JUKES T. H. Concerning the daily dose of folic acid. J Chronic Dis. 1961 Aug;14:283–283. doi: 10.1016/0021-9681(61)90159-x. [DOI] [PubMed] [Google Scholar]
  33. KNOWLES J. P., PRANKERD T. A., WESTALL R. G. Simplified method for detecting formiminoglutamic acid in urine as a test of folic-acid deficiency. Lancet. 1960 Aug 13;2(7146):347–348. doi: 10.1016/s0140-6736(60)91486-0. [DOI] [PubMed] [Google Scholar]
  34. KOHN J., MOLLIN D. L., ROSENBACH L. M. Conventional voltage electrophoresis for formiminoglutamic-acid determination in folic acid deficiency. J Clin Pathol. 1961 Jul;14:345–350. doi: 10.1136/jcp.14.4.345. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. LAYRISSE M., AGUERO O., BLUMENFELD N., WALLIS H., DUGARTE I., OJEDA A. Megaloblastic anemia of pregnancy: characteristics of pure megaloblastic anemia and megaloblastic anemia associated with iron deficiency. Blood. 1960 May;15:724–740. [PubMed] [Google Scholar]
  36. LUHBY A. L., COOPERMAN J. M., TELLER D. N. Histidine metabolic loading test to distinguish folic acid deficiency from vit. B12 in megaloblastic anemias. Proc Soc Exp Biol Med. 1959 Jun;101(2):350–352. doi: 10.3181/00379727-101-24936. [DOI] [PubMed] [Google Scholar]
  37. METZ J., STEVENS K., BRANDT V. Urinary formiminoglutamic acid in the megaloblastic anaemias associated with pregnancy and malnutrition. Br Med J. 1962 Dec 1;2(5317):1440–1441. doi: 10.1136/bmj.2.5317.1440. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. METZ J., STEVENS K., KRAWITZ S., BRANDT V. The plasma clearance of injected doses of folic acid as an index of folic acid deficiency. J Clin Pathol. 1961 Nov;14:622–625. doi: 10.1136/jcp.14.6.622. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. MILLER A., WAELSCH H. The transfer of the formimino group of formamidinoglutaric acid to tetrahydrofolic acid. Arch Biochem Biophys. 1956 Jul;63(1):263–266. doi: 10.1016/0003-9861(56)90033-9. [DOI] [PubMed] [Google Scholar]
  40. NARAYANAN M. S., RAMASARMA G. B., SHENOY K. G. Rise of serum folic acid-levels after injection of vitamin B12 in nutritional macrocytic anaemia. Nature. 1956 Dec 15;178(4546):1347–1348. doi: 10.1038/1781347a0. [DOI] [PubMed] [Google Scholar]
  41. NIEWEG H. O., FABER J. G., DE VRIES J. A., KROESE W. F. The relationship of vitamin B12 and folic acid in megaloblastic anemias. J Lab Clin Med. 1954 Jul;44(1):118–132. [PubMed] [Google Scholar]
  42. O'BRIEN J. S. Urinary excretion of folic and folinic acids in normal adults. Proc Soc Exp Biol Med. 1960 Jun;104:354–355. doi: 10.3181/00379727-104-25835. [DOI] [PubMed] [Google Scholar]
  43. PHILLIPS P. M., TOENNIES G., USDIN E. Multiplicity of the folic acid-active factors of blood. J Biol Chem. 1956 Aug;221(2):865–872. [PubMed] [Google Scholar]
  44. PHILLIPS P. M., TOENNIES G., USDIN E. Precursors of the folic acid-active factors of blood. J Biol Chem. 1956 Aug;221(2):855–863. [PubMed] [Google Scholar]
  45. PITNEY W. R., JOSKE R. A., MACKINNON N. L. Folic acid and other absorption tests in lymphosarcoma, chronic lymphocytic leukaemia, and some related conditions. J Clin Pathol. 1960 Sep;13:440–447. doi: 10.1136/jcp.13.5.440. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. RABINOWITZ J. C., TABOR H. The urinary excretion of formic acid and formiminoglutamic acid in folic acid deficiency. J Biol Chem. 1958 Jul;233(1):252–255. [PubMed] [Google Scholar]
  47. REGISTER U. D., SARETT H. P. Urinary excretion of vitamin B12, folic acid, and citrovorum factor in human subjects on various diets. Proc Soc Exp Biol Med. 1951 Aug;77(4):837–839. doi: 10.3181/00379727-77-18941. [DOI] [PubMed] [Google Scholar]
  48. SILVERMAN M., GARDINER R. C., BAKERMAN H. A. The nature of the glutamic acid excreted in folic acid deficiency. J Biol Chem. 1952 Feb;194(2):815–821. [PubMed] [Google Scholar]
  49. SILVERMAN M., GARDINER R. C., CONDIT P. T. A method for the detection of N-formiminoglutamic acid in urine. J Natl Cancer Inst. 1958 Jan;20(1):71–77. [PubMed] [Google Scholar]
  50. SIMPSON R. E., SCHWEIGERT B. S. Folic acid metabolism studies; occurrence of blood conjugases. Arch Biochem. 1949 Jan;20(1):32–40. [PubMed] [Google Scholar]
  51. SPRAY G. H., FOURMAN P., WITTS L. J. The excretion of small doses of folic acid. Br Med J. 1951 Jul 28;2(4725):202–205. doi: 10.1136/bmj.2.4725.202. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. SPRAY G. H., WITTS L. J. Excretion of formiminoglutamic acid as an index of folic-acid deficiency. Lancet. 1959 Oct 31;2(7105):702–704. doi: 10.1016/s0140-6736(59)92132-4. [DOI] [PubMed] [Google Scholar]
  53. SWENDSEID M. E., SWANSON A. L., MEYERS M. C., BETHELL F. H. The nutritional status of folic acid in persons with leukemia and its possible relation to effects of aminopterin therapy. Blood. 1952 Mar;7(3):307–310. [PubMed] [Google Scholar]
  54. TABOR H., WYNGARDEN L. A method for the determination of formiminoglutamic acid in urine. J Clin Invest. 1958 Jun;37(6):824–828. doi: 10.1172/JCI103670. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. TASKER P. W. Correlation of serum-vitamin B12 levels and urinary folic acid in nutritional megaloblastic anaemia. Lancet. 1955 Jul 9;269(6880):61–63. doi: 10.1016/s0140-6736(55)92164-4. [DOI] [PubMed] [Google Scholar]
  56. TOENNIES G., FRANK H. G., GALLANT D. L. On the folic acid activity of human blood. J Biol Chem. 1953 Jan;200(1):23–30. [PubMed] [Google Scholar]
  57. TOENNIES G., PHILLIPS P. M. Blood folic acid studies. V. Resolution of precursor and enzyme fractions of the blood folic acid system. J Biol Chem. 1959 Sep;234:2369–2372. [PubMed] [Google Scholar]
  58. USDIN E. Blood folic acid studies. VI. Chromatographic resolution of folic acid-active substances obtained from blood. J Biol Chem. 1959 Sep;234:2373–2376. [PubMed] [Google Scholar]
  59. WATERS A. H., MOLLIN D. L. Studies on the folic acid activity of human serum. J Clin Pathol. 1961 Jul;14:335–344. doi: 10.1136/jcp.14.4.335. [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. Wills L. TREATMENT OF "PERNICIOUS ANAEMIA OF PREGNANCY" AND "TROPICAL ANAEMIA". Br Med J. 1931 Jun 20;1(3676):1059–1064. doi: 10.1136/bmj.1.3676.1059. [DOI] [PMC free article] [PubMed] [Google Scholar]
  61. ZALUSKY R., HERBERT V. Megaloblastic anemia in scurvy with response to 50 microgm. of folic acid daily. N Engl J Med. 1961 Nov 23;265:1033–1038. doi: 10.1056/NEJM196111232652103. [DOI] [PubMed] [Google Scholar]

Articles from Bulletin of the World Health Organization are provided here courtesy of World Health Organization

RESOURCES