Chapter 100. Megaloblastic Anemias (Part 15) Folinic Acid (5-Formyl-Thf) This is a stable form of fully reduced folate. It is given orally or parenterally to overcome the toxic effects of methotrexate or other DHF reductase inhibitors. Prophylactic Folic Acid In many countries, food is fortified with folic acid (in grain or flour) to prevent neural tube defects. It is also used in chronic dialysis patients and in parenteral feeds. Prophylactic folic acid has been used to reduce homocysteine levels to prevent cardiovascular disease, but further data are needed to assess the benefit for this and for cognitive function in the elderly. Pregnancy Folic acid, 400 µg daily, should be given as a supplement before and throughout pregnancy. In women who have had a previous fetus with a neural tube defect, 5 mg daily is recommended when pregnancy is contemplated and throughout the subsequent pregnancy. Infancy and Childhood The incidence of folate deficiency is so high in the smallest premature babies during the first 6 weeks of life that folic acid (e.g., 1 mg daily) should be given routinely to those weighing <1500 g at birth and to larger premature babies who require exchange transfusions or develop feeding difficulties, infections, or vomiting and diarrhea. The World Health Organization currently recommends routine supplementation with iron and folic acid in children in countries where iron deficiency is common and child mortality, largely due to infectious diseases, is high. However, some studies suggest that where malaria rates are high, this approach may increase the incidence of severe illness and death. Even where malaria is rare, there appears to be no survival benefit. Megaloblastic Anemia Not Due to Cobalamin or Folate Deficiency or Altered Metabolism This may occur with many antimetabolic drugs (e.g.,. hydroxyurea, cytosine arabinoside, 6-mercaptopurine) that inhibit DNA replication. Antiviral nucleoside analogues used in treatment of HIV infection may also cause macrocytosis and megaloblastic marrow changes. In the rare disease orotic aciduria, two consecutive enzymes in purine synthesis are defective. The condition responds to therapy with uridine, which by-passes the block. In thiamine- responsive megaloblastic anemia, there is a genetic defect in the high-affinity thiamine transport (SLC19A2) gene. This causes defective RNA ribose synthesis through impaired activity of transketolase, a thiamine-dependent enzyme in the pentose cycle. This leads to reduced nucleic acid production. It may be associated with diabetes mellitus and deafness and the presence of many ringed sideroblasts in the marrow. The explanation is unclear for megaloblastic changes in the marrow in some patients with acute myeloid leukemia and myelodysplasia. Further Readings Bazzano LA et al: Ef fect of folic acid supplementation on risk of cardiovascular diseases. JAMA 296:2720, 2006 [PMID: 17164458] Bønaa KH et al: Homocysteine lowering and cardiovascular events after acute myocardial infarction. N Engl J Med 354:1578, 2006 [PMID: 18008384] Chan JCW et al: Pernicious anemia in Chinese: A study of 181 patients in a Hong Kong Hospital. Medicine 85:129, 2006 Durga J et al: Effect of 3- year folic acid supplementation on cognitive function in older adults in the FACIT trial: A randomized double- blind, controlled trial. Lancet 369:208, 2007 [PMID: 17240287] Hershko C et al: Variable hematologic presentation of autoimmune gastritis: Age- related progression from iron deficiency to cobalamin depletion. Blood 107:1673, 2006 [PMID: 16239424] Lonn E et al: Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med 354:1567, 2006 [PMID: 16531613] McMahon JA et al: A controlled trial of homocysteine lowering and cognitive performance. N Engl J Med 354:2764, 2006 [PMID: 16807413] Mills JL et al: Low vitamin B 12 concentrations in patients without anemia: The effect of folic acid fortification of grain. Am J Clin Nutr 77:1474, 2003 [PMID: 12791626] Rothenberg SP et al: Autoantibodies against folate receptors in women with a pregnancy complicated by a neural tube defect. N Engl J Med 350:134, 2004 [PMID: 14711912] Sazawal S et al: Effects of routine prophylactic supplementation with iron and folic acid on admission to hospital and mortality in preschool child mortality in Southern Nepal: Community-based, cluster-randomized, placebo- controlled trial. Lancet 367:144, 2006 Bibliography Chanarin I, Metz J: Diagnosis of cobalamin deficiency: The old and the new. Br J Haematol 97:695, 1997 [PMID: 9217166] Halfdanason TR et al : Hematologic manifestations of celiac disease. Blood 109:412, 2007 He Q et al: Amnionles function is required for cubilin brush- border expression and intrinsic factor-cobalamin (vitamin B 12 ) absorption in vivo. Blood 106:1447, 2005 [PMID: 15845892] Hershko C et al: Role of autoimmune gastritis, Helicobacter pylori and celiac disease in refractory or unexplained iron deficiency anemia. Haematologica 90:585, 2005 [PMID: 15921373] Solomon LR: Cobalamin- responsive disorders in the ambulatory case setting : Unreliability of cobalamin, methylmalonic acid and homocysteine testing. Blood 105:978, 2005 [PMID: 15466926] Toole JF et al: Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction and death: A Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial. JAMA 291:565, 2004 [PMID: 14762035] Wald DS et al: Folic acid, homocysteine, and cardiovascular disease: Judging causality in the face of inconclusive trial evidence. Br Med J 333: 1114, 2006 [PMID: 17124224] Whitehead VM: Acquired and inherited disorders of cobalamin and folate in children. Br J Haematol 134:125, 2006 [PMID: 16846473] Wickramasinghe SN: Morphology, biology and biochemistry of cobalamin and folate deficient bone marrow cells. Clin Haematol 8:441, 1995. [PMID: 8534956] . Chapter 100. Megaloblastic Anemias (Part 15) Folinic Acid (5-Formyl-Thf) This is a stable form of fully reduced. severe illness and death. Even where malaria is rare, there appears to be no survival benefit. Megaloblastic Anemia Not Due to Cobalamin or Folate Deficiency or Altered Metabolism This may. Antiviral nucleoside analogues used in treatment of HIV infection may also cause macrocytosis and megaloblastic marrow changes. In the rare disease orotic aciduria, two consecutive enzymes in purine