Megaloblastic anemia

• Vitamin B12 deficiency:
  • Achlorhydria-induced malabsorption
  • Deficient intake
  • Deficient intrinsic factor, a molecule produced by cells in the stomach that is required for B12 absorption (pernicious anemia or gastrectomy)
  • Coeliac disease
  • Biological competition for vitamin B12 by diverticulosis, fistula, intestinal anastomosis, or infection by the marine parasite Diphyllobothrium latum (fish tapeworm)
  • Selective vitamin B12 malabsorption (congenital—juvenile megaloblastic anemia 1—and drug-induced)
  • Chronic pancreatitis
  • Ileal resection and bypass
  • Nitrous oxide anesthesia (usually requires repeated instances).
• Folate deficiency:
  • Alcoholism
  • Deficient intake
  • Increased needs: pregnancy, infant, rapid cellular proliferation, and cirrhosis
  • Malabsorption (congenital and drug-induced)
  • Intestinal and jejunal resection
  • (indirect) Deficient thiamine and factors (e.g., enzymes) responsible for abnormal folate metabolism.
• Combined Deficiency: vitamin B12 & folate.
• Inherited Pyrimidine Synthesis Disorders: Orotic aciduria
• Inherited DNA Synthesis Disorders
• Toxins and Drugs:
  • Folic acid antagonists (methotrexate)
  • Purine synthesis antagonists (6-mercaptopurine, azathioprine)
  • Pyrimidine antagonists (cytarabine)
  • Phenytoin
  • Nitrous Oxide
• Erythroleukemia
• Inborn genetic mutations of the Methionine synthase gene
• Di Guglielmo's syndrome
• Congenital dyserythropoietic anemia
• Copper deficiency resulting from an excess of zinc from unusually high oral consumption of zinc-containing denture-fixation creams has been found to be a cause.[5][6]

There is a defect in DNA synthesis in the rapidly dividing cells and to a lesser extent, RNA and protein synthesis are also impaired. Therefore, unbalanced cell proliferation and impaired cell division occur as a result of arrested nuclear maturation so the cells show nuclear-cytoplasmic asynchrony.

In the bone marrow, most megaloblasts are destroyed prior to entering the peripheral blood (intramedullary hemolysis). Some can escape the bone marrow (macrocytes) to peripheral blood but they are destroyed by the reticulo-endothelial system (extramedullary hemolysis).

The gold standard for the diagnosis of Vitamin B₁₂ deficiency is a low blood level of Vitamin B₁₂. A low level of blood Vitamin B₁₂ is a finding that normally can and should be treated by injections, supplementation, or dietary or lifestyle advice, but it is not a diagnosis. Hypovitaminosis B₁₂ can result from a number of mechanisms, including those listed above. For determination of cause, further patient history, testing, and empirical therapy may be clinically indicated.

A measurement of methylmalonic acid (methylmalonate) can provide an indirect method for partially differentiating Vitamin B₁₂ and folate deficiencies. The level of methylmalonic acid is not elevated in folic acid deficiency. Direct measurement of blood cobalamin remains the gold standard because the test for elevated methylmalonic acid is not specific enough. Vitamin B₁₂ is one necessary prosthetic group to the enzyme methylmalonyl-coenzyme A mutase. Vitamin B₁₂ deficiency is but one among the conditions that can lead to dysfunction of this enzyme and a buildup of its substrate, methylmalonic acid, the elevated level of which can be detected in the urine and blood.

Due to the lack of available radioactive Vitamin B₁₂, the Schilling test is now largely a historical artifact. The Schilling test was performed in the past to help determine the nature of the vitamin B₁₂ deficiency. An advantage of the Schilling test was that it often included Vitamin B₁₂ with intrinsic factor.

• List of circulatory system conditions
• List of hematologic conditions

• GeneReview/NCBI/NIH/UW entry on Thiamine-Responsive Megaloblastic Anemia Syndrome
• Rare Anemias Foundation