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Megaloblastic anemia is an anemia (of macrocytic classification) which results from inhibition of DNA synthesis in red blood cell production. It is often due to deficiency of vitamin B12 and/or folic acid. It can be the result of a lack of intrinsic factor (which lack interferes with B12 absorption), causing pernicious anemia, or with other antimetabolites which poison DNA production, such as chemotherapeutic agents.

It is characterized by many large immature and dysfunctional red blood cells (megaloblasts) in the bone marrow, and also by hypersegmented or multisegmented neutrophils.

• nutritional defects (folic acid or vitamin B12 which is mainly from animal sources; vegans may require supplementation)
• chronic liver diseases
• alcoholism
• pregnancy
• decreased production of intrinsic factor (this disease entity is called pernicious anemia)
• intestinal malabsorption (due to an enteritis, celiac disease or other causes).
• fish tapeworm infestation (Diphyllobothrium latum)
• failure to replicate chromosomes due to lack of thymidine.
• Lesch-Nyhan Syndrome
• cytotoxic drugs interfering with DNA synthesis
• intestinal flora disruption due to antibiotic use

The blood film can point towards vitamin deficiency:

• Decreased red blood cell (RBC) count and hemoglobin levels
• Increased mean corpuscular volume (MCV, >95 fl) and mean corpuscular hemoglobin (MCH)
• The reticulocyte count is normal
• The platelet count may be reduced.
• Neutrophil granulocytes may show multisegmented nuclei ("senile neutrophil"). This is thought to be due to decreased production and a compensatory prolonged lifespan for circulating neutrophils.
• Anisocytosis (increased variation in RBC size) and poikilocytosis (abnormally shaped RBCs).
• Macrocytes (larger than normal RBCs) are present.
• Ovalocytes (oval shaped RBCs) are present.
• Bone marrow (not normally checked in a patient suspected of megaloblastic anemia) shows megaloblastic hyperplasia.
• Howell-Jolly bodies (chromosomal remnant) also present.

Blood chemistries will also show:

• Increased homocysteine and methylmalonic acid in B12 deficiency
• Increased homocysteine in folate defiency

The Schilling test was performed in the past to determine the nature of the vitamin B12 deficiency, but due to the lack of available radioactive B12, it is now largely a historical artifact. Vitamin B₁₂ is a necessary prosthetic group to the enzyme methylmalonyl-coenzyme A mutase. B₁₂ deficiency leads 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. Since the level of methylmalonic acid is not elevated in folic acid deficiency, this test provides a one tool in differentiating the two. However, since the test for elevated methylmalonic acid is not specific enough, the gold standard for the diagnosis of B12 deficiency is a low blood level of B12. Unlike the Shilling test, which often included B12 with intrinsic factor, a low level of blood B12 gives no clue as to the etiology of the low B12, which can from several causes.