What causes macrocytosis (large red blood cell condition)?

From the Guidelines

Macrocytosis is primarily caused by vitamin B12 deficiency, folate deficiency, and other conditions that impair DNA synthesis, leading to abnormally large red blood cells. The most common causes of macrocytosis include:

• Vitamin B12 deficiency
• Folate deficiency
• Alcoholism
• Liver disease
• Certain medications like methotrexate, anticonvulsants, and some chemotherapy drugs
• Hypothyroidism
• Myelodysplastic syndromes
• Reticulocytosis (increased production of immature red blood cells) 1. In B12 and folate deficiencies, DNA synthesis is impaired, causing cells to grow larger but divide more slowly 1. Alcohol directly damages red blood cell membranes and interferes with folate metabolism 1. Liver disease affects red blood cell membrane composition, leading to larger cells. Some medications disrupt DNA synthesis in developing red blood cells. Blood tests measuring B12, folate, liver function, and thyroid hormones can help determine the specific cause, which is important for proper treatment 1. Macrocytosis is often detected during routine blood work when the mean corpuscular volume (MCV) exceeds 100 femtoliters. Key laboratory tests for diagnosing the cause of macrocytosis include:
• Complete blood count (CBC) with MCV
• Reticulocyte count
• Serum ferritin
• Transferrin saturation
• CRP
• Vitamin B12 and folate levels
• Liver function tests
• Thyroid hormone levels 1. Treatment of macrocytosis depends on the underlying cause, and may involve vitamin B12 or folate supplementation, discontinuation of offending medications, or treatment of underlying liver disease or hypothyroidism 1.

From the FDA Drug Label

Impairment of thymidylate synthesis in patients with folic acid deficiency is thought to account for the defective deoxyribonucleic acid (DNA) synthesis that leads to megaloblast formation and megaloblastic and macrocytic anemias.

Folic acid deficiency is thought to cause macrocytosis (large red blood cell condition) by impairing thymidylate synthesis, leading to defective DNA synthesis and resulting in megaloblastic and macrocytic anemias 2.

• Key factors:
  • Folic acid deficiency: leads to impaired thymidylate synthesis
  • Impaired thymidylate synthesis: results in defective DNA synthesis
  • Defective DNA synthesis: causes megaloblast formation and macrocytic anemias

From the Research

Causes of Macrocytosis

The causes of macrocytosis, a condition characterized by large red blood cells, can be diverse. Some of the common causes include:

• Vitamin B12 and folate deficiencies 3, 4, 5, 6, 7
• Alcoholism 3, 4, 6
• Liver disease 4, 5
• Various forms of drug therapy, including zidovudine 3, 4, 6
• Hypothyroidism 4
• Primary bone marrow dysplasias, such as myelodysplasia and myeloproliferative disorders 4
• Reticulocytosis 5
• Malignant neoplasms 6
• Congenital abnormalities of cobalamin and folate metabolism 7

Diagnostic Approach

To diagnose the underlying cause of macrocytosis, the following tests and examinations can be helpful:

• History and physical examination 4
• Vitamin B12 level 4, 5
• Reticulocyte count 4, 5
• Peripheral smear 4, 5
• Serum and red cell folate determinations 5
• Schilling test or plasma uptake test to pinpoint the cause of vitamin B12 deficiency 5