Folate deficiency beyond megaloblastic anemia: hyperhomocysteinemia and other manifestations of dysfunctional folate status

Semin Hematol. 1999 Jan;36(1):47-64.


Folate plays a key role in nucleic acid synthesis. As a consequence, the most conspicuous complication of folate deficiency or of derangements of folate metabolism is megaloblastic macrocytic anemia caused by interdiction of normal proliferation of rapidly dividing bone marrow cells. Other rapidly dividing cells, including those in the gastrointestinal tract, may also be affected by the megaloblastic process. This may result in malabsorption. However, there is mounting evidence to indicate that there are other earlier manifestations of folate deficiency or of longstanding suboptimal folate nutrition. Chief among these manifestations of folate deficiency are an increased predisposition to occlusive vascular disease and thrombosis, which have been linked to increased levels of homocysteine found in folate deficiency and abnormal states of folate metabolism. In addition, folate deficiency, previously considered free of neurological consequences, is now known to be associated with disturbances of mood, and even spinal cord syndromes similar to those seen in vitamin B12 deficiency. Finally, there is both experimental and clinical evidence to suggest that folate deficiency may interfere with immunologic status and may be associated with an increased predisposition to neoplasia. Nutritional as well as genetic factors may contribute to these various nonhematological manifestations of folate insufficiency.

Publication types

  • Review

MeSH terms

  • Anemia, Megaloblastic* / complications
  • Cardiovascular Diseases / etiology
  • Congenital Abnormalities / etiology
  • Female
  • Folic Acid Deficiency / complications
  • Folic Acid Deficiency / diagnosis*
  • Humans
  • Hyperhomocysteinemia* / complications
  • Methylenetetrahydrofolate Reductase (NADPH2)
  • Nervous System Diseases / etiology
  • Oxidoreductases Acting on CH-NH Group Donors / deficiency
  • Pregnancy
  • Pregnancy Complications


  • Oxidoreductases Acting on CH-NH Group Donors
  • Methylenetetrahydrofolate Reductase (NADPH2)