What causes macrocytic anemia?

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Last updated: May 11, 2025View editorial policy

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From the Guidelines

Macrocytic anemia is primarily caused by vitamin B12 and folate deficiency, which are the most common causes of megaloblastic, macrocytic anemia. The most recent and highest quality study, 1, highlights the importance of treating vitamin B12 deficiency immediately, especially in cases with possible neurological involvement. Other causes of macrocytic anemia include alcoholism, liver disease, and certain medications such as methotrexate, phenytoin, and chemotherapy drugs.

Some key points to consider when evaluating macrocytic anemia include:

  • Vitamin B12 deficiency can be treated with hydroxocobalamin 1 mg intramuscularly, administered on alternate days until there is no further improvement, then every 2 months 1
  • Folate deficiency may indicate non-adherence with daily multivitamin and mineral supplements or malabsorption, and can be treated with oral folic acid 5 mg daily for a minimum of 4 months 1
  • Other conditions such as myelodysplastic syndromes, hypothyroidism, and reticulocytosis can also cause macrocytic anemia, as noted in 1 and 1

It is essential to identify and address the underlying cause of macrocytic anemia to provide effective treatment and improve patient outcomes. Treatment should prioritize addressing the underlying cause, such as vitamin B12 injections for B12 deficiency or folate supplementation for folate deficiency.

From the Research

Causes of Macrocytic Anemia

  • Megaloblastic anemia, which is caused by deficiency or impaired utilization of vitamin B12 and/or folate 2, 3
  • Nonmegaloblastic macrocytic anemia, which is caused by various diseases such as:
    • Myelodysplastic syndrome (MDS) 2, 3
    • Liver dysfunction 2, 3
    • Alcoholism 2, 3
    • Hypothyroidism 2, 3
    • Certain drugs 2
    • Inherited disorders of DNA synthesis 2
  • Release of reticulocytes in the normal physiologic response to acute anemia 3

Association with Vitamin B12 and Folate Deficiency

  • Low vitamin B12 status is significantly associated with anemia and macrocytosis 4
  • Low folate status is significantly associated with anemia and macrocytosis 4
  • Determining a hematologic cutoff value for vitamin B12 and folate may help physicians in clinical practice 4

References

Guideline

Guideline Directed Topic Overview

Dr.Oracle Medical Advisory Board & Editors, 2025

Research

Diagnosis and treatment of macrocytic anemias in adults.

Journal of general and family medicine, 2017

Research

Anemia: Macrocytic Anemia.

FP essentials, 2023

Professional Medical Disclaimer

This information is intended for healthcare professionals. Any medical decision-making should rely on clinical judgment and independently verified information. The content provided herein does not replace professional discretion and should be considered supplementary to established clinical guidelines. Healthcare providers should verify all information against primary literature and current practice standards before application in patient care. Dr.Oracle assumes no liability for clinical decisions based on this content.

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