Anemia is strictly defined as a decrease in red blood cell (RBC) mass or blood hemoglobin concentration. The prevalence of anemia in population studies of healthy, nonpregnant people depends on the hemoglobin (Hb) levels chosen for the lower limit of normal values. The World Health Organization (WHO) anemia definition is Hb levels <12.0 g/dL in women and <13.0 g/dL in men.

Anemia is a manifestation of an underlying condition and treatment depends on discover the cause

Cobalamin, folic acid deficiencies, and certain drugs are the most common causes of megaloblastic anemia, a macrocytic anemia.

Macrocytosis, generally defined as a mean corpuscular volume greater than 100 fL. The causes of macrocytosis can be classified as megaloblastic and nonmegaloblastic. Megaloblastic processes have macroovalocytes and hypersegmented neutrophils on the peripheral smear, which are absent in nonmegaloblastic macrocytic clinical conditions. Megaloblastic macrocytic anemia is caused by folate and B12 deficiency, and orotic aciduria.

Myelodysplastic syndrome is a nonmegaloblastic macrocytic clinical condition. An important clue in patients workup is that usually pancytopenia is presented, rather than isolated anemia. Alcoholism, liver disease, and Diamond-Blackfan anemia are also causes of nonmegaloblastic macrocytic anemia.

B12 or Cobalamin

  • Type of Vitamin: water-soluble.
  • Main dietary sources: animal products.
  • Metabolism: it cannot be produced by the human body, and must be obtained from the diet. It is absorbed by the ileum when it is bound by intrinsic factor, which is produced by the parietal cells of the gastric mucosa. B12 is stored in the liver for ~ 3–4 years.
  • High-risk population for Vitamin B12 deficiency anemia: malabsorption syndromes (eg, sprue, enteritis, Diphyllobothrium latum), veganism, surgical resection of terminal ileum and lack of intrinsic factor (pernicious anemia, gastric bypass surgery)
  • Pernicious anemia is the most common cause of Vitamin B12 deficiency. Loss of parietal cells characterizes pernicious anemia, which leads to insufficient absorption of vitamin B12, which then leads to vitamin B12 deficiency over time. Pernicious anemia is commonly caused by auto-immune atrophic gastritis, in which autoantibodies are directed against parietal cells and intrinsic factor.
  • Key differences with folate deficiency anemia: vitamin B12 deficiency is associated with increased serum homocysteine and methylmalonic acid level as well with neurological symptoms such as numbness and paresthesias of the extremities (worse in legs), decreased vibratory sensation and spastic paresis.

B9 or Folate

  • Type of Vitamin: water-soluble.
  • Main dietary sources: found in leafy green vegetables.
  • Metabolism: the daily requirement for adults is about 400 micrograms per day from foods or dietary supplements in order to replenish the daily degradation and loss through urine and bile. Storage is limited, and folate deficiency develops about 3-4 weeks after the cessation of folate intake and it is absorbed in the jejunum.
  • High-risk population for Folate deficiency anemia: It’s the most common vitamin deficiency in the United States. Folate deficiency can be caused by poor nutritional intake, malabsorption, amyloidosis, inflammatory bowel disease, and alcoholism. Some medications that are used to treat seizure disorders, cancer, and autoimmune diseases can lead to folate deficiency, for example, phenytoin, sulfonamides, methotrexate, trimethoprim, pyrimethamine.
  • Neural tube defects in pregnancy: neural tube defects (NTDs) are common complex congenital malformations of the central nervous system resulting from the failure of the neural tube closure during embryogenesis.Observational studies and controlled trials have shown that neural tube defects can be reduced by 80% or more when folic acid supplementation is started before conception.
  • Key differences with folate deficiency anemia: it is associated with increased homocysteine serum and normal methylmalonic acid.folate and vitamin B12 deficiency neurological manifestations overlap and include cognitive impairment, dementia, depression, and, less commonly, peripheral neuropathy and subacute combined degeneration of the spinal cord.

Folates and cobalamin have fundamental roles in central nervous system function, especially in purine, thymidine, nucleotides, and DNA synthesis, genomic and nongenomic methylation and, therefore, in tissue growth, differentiation, and repair. In both vitamin deficiency, there is often an association between the neuropsychiatric and the hematologic complications.


  • Nagao T, Hirokawa M. Diagnosis and treatment of macrocytic anemias in adults. Journal of General and Family Medicine. 2017;18(5):200-204. doi:10.1002/jgf2.31. (link)
  • Kaferle J, Strzoda CE. Evaluation of macrocytosis. Am Fam Physician. 2009 Feb 1;79(3):203-8. Review (link)
  • Cappellini MD, Motta I. Anemia in Clinical Practice-Definition and Classification: Does Hemoglobin Change With Aging? Semin Hematol. 2015 Oct;52(4):261-9. doi: 10.1053/j.seminhematol.2015.07.006. (link)
  • The USPSTF recommendations about Folic Acid to Prevent Neural Tube Defects (link)
  • Imbard, A., Benoist, J.-F., & Blom, H. J. (2013). Neural Tube Defects, Folic Acid and Methylation. International Journal of Environmental Research and Public Health, 10(9), 4352–4389. (link)
  • Reynolds EH. The neurology of folic acid deficiency. Handb Clin Neurol. 2014;120:927-43. doi: 10.1016/B978-0-7020-4087-0.00061-9. Review. (link) 

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